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Entry
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- *164757 - B-RAF PROTOONCOGENE, SERINE/THREONINE KINASE; BRAF
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*164757</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/164757">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000157764;t=ENST00000646891" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=673" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=164757" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000157764;t=ENST00000646891" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001354609,NM_001374244,NM_001374258,NM_001378467,NM_001378468,NM_001378469,NM_001378470,NM_001378471,NM_001378472,NM_001378473,NM_001378474,NM_001378475,NM_004333,XM_017012559,XM_047420766,XM_047420767,XM_047420768,XM_047420769,XM_047420770" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_004333" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=164757" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01264&isoform_id=01264_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/BRAF" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/29486,179535,4309920,5441948,7271193,33188459,41350055,41387220,50403720,51094777,75516780,85567150,119604370,119604371,187473252,251731613,291048863,307334902,311697325,323520015,661914241,1034656685,1192789093,1192789095,1192789097,1192789099,1192789101,1192789103,1237938074,1741710882,1743116012,1810812854,1810812862,1810812868,1810812870,1810812874,1810812878,1810812880,1810812884,1810812889,2217368282,2217368284,2217368286,2217368288,2217368290,2430294550,2462615832,2462615834,2462615836,2462615838,2462615840,2462615842" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P15056" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=673" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000157764;t=ENST00000646891" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=BRAF" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=BRAF" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+673" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/BRAF" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:673" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/673" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr7&hgg_gene=ENST00000644969.2&hgg_start=140713328&hgg_end=140924929&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:1097" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:1097" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/braf" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=164757[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=164757[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/BRAF/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000157764" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=BRAF" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=BRAF" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=BRAF" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=BRAF&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA25408" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:1097" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0003079.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:88190" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/BRAF#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:88190" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/673/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA001512/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=673" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00003030;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040805-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:673" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=BRAF&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 403770008<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
|
164757
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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B-RAF PROTOONCOGENE, SERINE/THREONINE KINASE; BRAF
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1<br />
|
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ONCOGENE BRAF<br />
|
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BRAF1<br />
|
|
RAFB1
|
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</span>
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</h4>
|
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</div>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
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</span>
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</p>
|
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</div>
|
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<div>
|
|
<span class="h3 mim-font">
|
|
BRAF/AKAP9 FUSION GENE, INCLUDED
|
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</span>
|
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</div>
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<div>
|
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<span class="h4 mim-font">
|
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|
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BRAF/KIAA1549 FUSION GENE, INCLUDED
|
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</span>
|
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</div>
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=BRAF" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BRAF</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/7/742?start=-3&limit=10&highlight=742">7q34</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:140713328-140924929&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">7:140,713,328-140,924,929</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=211980,115150,114500,613707,155600,211980,613706" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
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<tr>
|
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<td rowspan="7">
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<span class="mim-font">
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<a href="/geneMap/7/742?start=-3&limit=10&highlight=742">
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7q34
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Adenocarcinoma of lung, somatic
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<a href="/entry/114500"> 114500 </a>
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<a href="/entry/613707"> 613707 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Nonsmall cell lung cancer, somatic
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<span class="mim-font">
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<a href="/entry/211980"> 211980 </a>
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<span class="mim-font">
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Noonan syndrome 7
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<span class="mim-font">
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<a href="/entry/613706"> 613706 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/164757" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/164757" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>Using an oligomer unique to the BRAF kinase domain, <a href="#77" class="mim-tip-reference" title="Sithanandam, G., Kolch. W., Duh, F.-M., Rapp, U. R. <strong>Complete coding sequence of a human B-raf cDNA and detection of B-raf protein kinase with isozyme specific antibodies.</strong> Oncogene 5: 1775-1780, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2284096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2284096</a>]" pmid="2284096">Sithanandam et al. (1990)</a> cloned full-length BRAF from a testis cDNA library. The deduced 651-amino acid protein has a calculated molecular mass of 72.5 kD. It contains all 3 conserved regions of RAF protein kinases: a putative zinc finger region, a serine/threonine-rich region, and a C-terminal kinase domain, which includes a putative ATP-binding site and a catalytic lysine. In addition, the N terminus of BRAF is serine-rich, and it has a consensus CDC2 (CDK1; <a href="/entry/116940">116940</a>) phosphorylation motif. Northern blot analysis detected transcripts of 10 and 13 kb in cerebrum, fetal brain, and placenta and transcripts of 2.6 and 4.5 kb in testis. Testis also showed lower expression of the 10- and 13-kb transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2284096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Eychene, A., Barnier, J. V., Apiou, F., Dutrillaux, B., Calothy, G. <strong>Chromosomal assignment of two human B-raf(Rmil) proto-oncogene loci: B-raf-1 encoding the p94(Braf/Rmil) and B-raf-2, a processed pseudogene.</strong> Oncogene 7: 1657-1660, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1630826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1630826</a>]" pmid="1630826">Eychene et al. (1992)</a> stated that the BRAF gene is the human homolog of the avian c-Rmil protooncogene encoding a 94-kD serine/threonine kinase detected in avian cells. This protein contains amino-terminal sequences not found in other proteins of the mil/raf gene family. These sequences are encoded by 3 exons in the avian genome. <a href="#17" class="mim-tip-reference" title="Eychene, A., Barnier, J. V., Apiou, F., Dutrillaux, B., Calothy, G. <strong>Chromosomal assignment of two human B-raf(Rmil) proto-oncogene loci: B-raf-1 encoding the p94(Braf/Rmil) and B-raf-2, a processed pseudogene.</strong> Oncogene 7: 1657-1660, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1630826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1630826</a>]" pmid="1630826">Eychene et al. (1992)</a> reported that these 3 exons are conserved in the human BRAF gene and that they encode an amino acid sequence similar to that of the avian gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1630826" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneFunctionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<p>Fusion of PML (<a href="/entry/102578">102578</a>) and TIF1A (<a href="/entry/603406">603406</a>) to RARA (<a href="/entry/180240">180240</a>) and BRAF, respectively, results in the production of PML-RAR-alpha and TIF1-alpha-B-RAF (T18) oncoproteins. <a href="#98" class="mim-tip-reference" title="Zhong, S., Delva, L., Rachez, C., Cenciarelli, C., Gandini, D., Zhang, H., Kalantry, S., Freedman, L. P., Pandolfi, P. P. <strong>A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RAR-alpha and T18 oncoproteins.</strong> Nature Genet. 23: 287-295, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10610177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10610177</a>] [<a href="https://doi.org/10.1038/15463" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10610177">Zhong et al. (1999)</a> showed that PML, TIF1-alpha, and RXR-alpha (<a href="/entry/180245">180245</a>)/RAR-alpha function together in a retinoic acid-dependent transcription complex. PML interacts with TIF1-alpha and CREB-binding protein (CBP; <a href="/entry/600140">600140</a>). T18, similar to PML-RAR-alpha, disrupts the retinoic acid-dependent activity of this complex in a dominant-negative manner, resulting in a growth advantage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10610177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a genomewide RNA interference screen, <a href="#87" class="mim-tip-reference" title="Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M., Green, M. R. <strong>Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7.</strong> Cell 132: 363-374, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18267069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18267069</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18267069[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2007.12.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18267069">Wajapeyee et al. (2008)</a> identified 17 factors required for oncogenic BRAF to induce senescence in primary fibroblasts and melanocytes. One of these factors is an F-box protein, FBXO31 (<a href="/entry/609102">609102</a>), a candidate tumor suppressor encoded in 16q24.3, a region in which there is loss of heterozygosity in breast, ovarian, hepatocellular, and prostate cancers. <a href="#72" class="mim-tip-reference" title="Santra, M. K., Wajapeyee, N., Green, M. R. <strong>F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage.</strong> Nature 459: 722-725, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412162</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412162[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412162">Santra et al. (2009)</a> studied the cellular role of FBXO31, identified its target substrate, and determined the basis for its growth inhibitory activity. They showed that ectopic expression of FBXO31 acts through a proteasome-directed pathway to mediate the degradation of cyclin D1 (<a href="/entry/168461">168461</a>), an important regulator of progression from G1 to S phase, resulting in arrest in G1. Cyclin D1 degradation results from a direct interaction with FBXO31 and is dependent on the F-box motif of FBXO31 and phosphorylation of cyclin D1 at thr286, which is required for cyclin D1 proteolysis. The involvement of the DNA damage response in oncogene-induced senescence prompted <a href="#72" class="mim-tip-reference" title="Santra, M. K., Wajapeyee, N., Green, M. R. <strong>F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage.</strong> Nature 459: 722-725, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412162</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412162[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412162">Santra et al. (2009)</a> to investigate the role of FBXO31 in DNA repair. They found that DNA damage induced by gamma-irradiation results in increased FBXO31 levels, which requires phosphorylation of FBXO31 by the DNA damage response-initiating kinase ATM (<a href="/entry/607585">607585</a>). RNAi-mediated knockdown of FBXO31 prevents cells from undergoing efficient arrest in G1 after gamma-irradiation and markedly increases sensitivity to DNA damage. Finally, <a href="#72" class="mim-tip-reference" title="Santra, M. K., Wajapeyee, N., Green, M. R. <strong>F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage.</strong> Nature 459: 722-725, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412162</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412162[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412162">Santra et al. (2009)</a> showed that a variety of DNA damaging agents all result in a large increase in FBXO31 levels, indicating that induction of FBXO31 is a general response to genotoxic stress. <a href="#72" class="mim-tip-reference" title="Santra, M. K., Wajapeyee, N., Green, M. R. <strong>F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage.</strong> Nature 459: 722-725, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412162</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412162[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412162">Santra et al. (2009)</a> concluded that their results reveal FBXO31 as a regulator of the G1/S transition that is specifically required for DNA damage-induced growth arrest. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18267069+19412162" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Drosophila Schneider S2 cells, <a href="#68" class="mim-tip-reference" title="Rajakulendran, T., Sahmi, M., Lefrancois, M., Sicheri, F., Therrien, M. <strong>A dimerization-dependent mechanism drives RAF catalytic activation.</strong> Nature 461: 542-545, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19727074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19727074</a>] [<a href="https://doi.org/10.1038/nature08314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19727074">Rajakulendran et al. (2009)</a> demonstrated that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which they termed the side-to-side dimer. <a href="#68" class="mim-tip-reference" title="Rajakulendran, T., Sahmi, M., Lefrancois, M., Sicheri, F., Therrien, M. <strong>A dimerization-dependent mechanism drives RAF catalytic activation.</strong> Nature 461: 542-545, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19727074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19727074</a>] [<a href="https://doi.org/10.1038/nature08314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19727074">Rajakulendran et al. (2009)</a> also showed that RAF side-to-side dimer formation is essential for aberrant signaling by oncogenic BRAF mutants, and identified an oncogenic mutation (G558K, <a href="#10" class="mim-tip-reference" title="Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., Davis, N., Dicks, E., and 40 others. <strong>Mutations of the BRAF gene in human cancer.</strong> Nature 417: 949-954, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12068308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12068308</a>] [<a href="https://doi.org/10.1038/nature00766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12068308">Davies et al., 2002</a>) that acts specifically by promoting side-to-side dimerization. <a href="#68" class="mim-tip-reference" title="Rajakulendran, T., Sahmi, M., Lefrancois, M., Sicheri, F., Therrien, M. <strong>A dimerization-dependent mechanism drives RAF catalytic activation.</strong> Nature 461: 542-545, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19727074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19727074</a>] [<a href="https://doi.org/10.1038/nature08314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19727074">Rajakulendran et al. (2009)</a> concluded that their data identified the side-to-side dimer interface of RAF as a potential therapeutic target for intervention in BRAF-dependent tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12068308+19727074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate how ultraviolet radiation (UVR) accelerates oncogenic BRAF-driven melanomagenesis (CMM1; <a href="/entry/155600">155600</a>), <a href="#86" class="mim-tip-reference" title="Viros, A., Sanchez-Laorden, B., Pedersen, M., Furney, S. J., Rae, J., Hogan, K., Ejiama, S., Girotti, M. R., Cook, M., Dhomen, N., Marais, R. <strong>Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.</strong> Nature 511: 478-482, 2014. Note: Erratum: Nature 519: 118 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24919155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24919155</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24919155[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24919155">Viros et al. (2014)</a> used a BRAF mutant (V600E; <a href="#0001">164757.0001</a>) mouse model. In mice expressing the V600E mutation in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. <a href="#86" class="mim-tip-reference" title="Viros, A., Sanchez-Laorden, B., Pedersen, M., Furney, S. J., Rae, J., Hogan, K., Ejiama, S., Girotti, M. R., Cook, M., Dhomen, N., Marais, R. <strong>Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.</strong> Nature 511: 478-482, 2014. Note: Erratum: Nature 519: 118 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24919155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24919155</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24919155[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24919155">Viros et al. (2014)</a> showed that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma but provided only partial protection. The UVR-exposed tumors showed increased numbers of single-nucleotide variants, and <a href="#86" class="mim-tip-reference" title="Viros, A., Sanchez-Laorden, B., Pedersen, M., Furney, S. J., Rae, J., Hogan, K., Ejiama, S., Girotti, M. R., Cook, M., Dhomen, N., Marais, R. <strong>Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.</strong> Nature 511: 478-482, 2014. Note: Erratum: Nature 519: 118 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24919155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24919155</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24919155[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24919155">Viros et al. (2014)</a> observed mutations in Trp53 (TP53; <a href="/entry/191170">191170</a>) in approximately 40% of cases. TP53 is an accepted UVR target in human nonmelanoma skin cancer but was not thought to play a major role in melanoma. However, <a href="#86" class="mim-tip-reference" title="Viros, A., Sanchez-Laorden, B., Pedersen, M., Furney, S. J., Rae, J., Hogan, K., Ejiama, S., Girotti, M. R., Cook, M., Dhomen, N., Marais, R. <strong>Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.</strong> Nature 511: 478-482, 2014. Note: Erratum: Nature 519: 118 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24919155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24919155</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24919155[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24919155">Viros et al. (2014)</a> showed that in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that in humans TP53 mutations are linked to evidence of UVR-induced DNA damage in melanoma. Thus, the authors provided mechanistic insight into epidemiologic data linking UVR to acquired nevi in humans. Furthermore, they identified TP53/Trp53 as a UVR target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. <a href="#86" class="mim-tip-reference" title="Viros, A., Sanchez-Laorden, B., Pedersen, M., Furney, S. J., Rae, J., Hogan, K., Ejiama, S., Girotti, M. R., Cook, M., Dhomen, N., Marais, R. <strong>Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.</strong> Nature 511: 478-482, 2014. Note: Erratum: Nature 519: 118 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24919155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24919155</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24919155[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24919155">Viros et al. (2014)</a> stated that their study validated public health campaigns that promote sunscreen protection for individuals at risk of melanoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24919155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Karreth, F. A., Reschke, M., Ruocco, A., Ng, C., Chapuy, B., Leopold, V., Sjoberg, M., Keane, T. M., Verma, A., Ala, U., Tay, Y., Wu, D., and 11 others. <strong>The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo.</strong> Cell 161: 319-332, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25843629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25843629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25843629[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2015.02.043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25843629">Karreth et al. (2015)</a> noted that pseudogenes have the potential to posttranscriptionally regulate their parental transcripts. They found that the human and mouse BRAF pseudogenes, BRAFP1 (<a href="/entry/300956">300956</a>) and Brafrs1, respectively, increased expression of BRAF and phosphorylated ERK and stimulated proliferation in human and mouse cells. In vitro, BRAFP1 and Brafrs1 upregulated BRAF expression and BRAF signaling by acting as decoys that sequestered microRNAs (miRNAs) shared between BRAF and its pseudogenes, thus relieving miRNA-dependent BRAF repression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25843629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#97" class="mim-tip-reference" title="Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., Roper, J., Chio, I. I. C., Giannopoulou, E. G., Rago, C., Muley, A., Asara, J. M., Paik, J., Elemento, O., Chen, Z., Pappin, D. J., Dow, L. E., Papadopoulos, N., Gross, S. S., Cantley, L. C. <strong>Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.</strong> Science 350: 1391-1396, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26541605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26541605</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26541605[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aaa5004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26541605">Yun et al. (2015)</a> found that cultured human colorectal cancer cells harboring KRAS (<a href="/entry/190070">190070</a>) or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 (<a href="/entry/138140">138140</a>) glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wildtype cells. High-dose vitamin C impairs tumor growth in Apc/Kras(G12D) mutant mice. <a href="#97" class="mim-tip-reference" title="Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., Roper, J., Chio, I. I. C., Giannopoulou, E. G., Rago, C., Muley, A., Asara, J. M., Paik, J., Elemento, O., Chen, Z., Pappin, D. J., Dow, L. E., Papadopoulos, N., Gross, S. S., Cantley, L. C. <strong>Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.</strong> Science 350: 1391-1396, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26541605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26541605</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26541605[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aaa5004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26541605">Yun et al. (2015)</a> suggested that their results provided a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26541605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MEK Inhibition</em></strong></p><p>
|
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Using small-molecule inhibitors of MAPK/ERK kinase (MEK; see <a href="/entry/176872">176872</a>) and an integrated genetic and pharmacologic analysis, <a href="#78" class="mim-tip-reference" title="Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., Golub, T. R., Sebolt-Leopold, J., Sellers, W. R., Rosen, N. <strong>BRAF mutation predicts sensitivity to MEK inhibition.</strong> Nature 439: 358-362, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16273091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16273091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16273091[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature04304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16273091">Solit et al. (2006)</a> found that mutation of BRAF is associated with enhanced and selective sensitivity to MEK inhibition when compared to either wildtype cells or cells harboring a RAS mutation. This MEK dependency was observed in BRAF mutant cells regardless of tissue lineage, and correlated with both downregulation of cyclin D1 (<a href="/entry/168461">168461</a>) protein expression and the induction of G1 arrest. Pharmacologic MEK inhibition completely abrogated tumor growth in BRAF mutant xenografts, whereas RAS (see <a href="/entry/190020">190020</a>) mutant tumors were only partially inhibited. <a href="#78" class="mim-tip-reference" title="Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., Golub, T. R., Sebolt-Leopold, J., Sellers, W. R., Rosen, N. <strong>BRAF mutation predicts sensitivity to MEK inhibition.</strong> Nature 439: 358-362, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16273091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16273091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16273091[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature04304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16273091">Solit et al. (2006)</a> concluded that their data suggested an exquisite dependency on MEK activity in BRAF mutant tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16273091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ball, D. W., Jin, N., Rosen, D. M., Dackiw, A., Sidransky, D., Xing, M., Nelkin, B. D. <strong>Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244.</strong> J. Clin. Endocr. Metab. 92: 4712-4718, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17878251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17878251</a>] [<a href="https://doi.org/10.1210/jc.2007-1184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17878251">Ball et al. (2007)</a> examined MEK inhibition and cell growth in 4 BRAF mutant (V600E; <a href="#0001">164757.0001</a>) and 2 BRAF wildtype thyroid cancer cell lines and in xenografts from a BRAF mutant cell line after treatment with the potent MEK1/2 inhibitor AZD6244. AZD6244 potently inhibited MEK1/2 activity in thyroid cancer cell lines regardless of BRAF mutation status. <a href="#1" class="mim-tip-reference" title="Ball, D. W., Jin, N., Rosen, D. M., Dackiw, A., Sidransky, D., Xing, M., Nelkin, B. D. <strong>Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244.</strong> J. Clin. Endocr. Metab. 92: 4712-4718, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17878251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17878251</a>] [<a href="https://doi.org/10.1210/jc.2007-1184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17878251">Ball et al. (2007)</a> concluded that AZD6244 inhibits the MEK-ERK pathway across a spectrum of thyroid cancer cells. MEK inhibition is cytostatic in papillary thyroid cancer and anaplastic thyroid cancer cells bearing a BRAF mutation and may have less impact on thyroid cancer cells lacking this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17878251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Leboeuf, R., Baumgartner, J. E., Benezra, M., Malaguarnera, R., Solit, D., Pratilas, C. A., Rosen, N., Knauf, J. A., Fagin, J. A. <strong>BRAF(V600E) mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines.</strong> J. Clin. Endocr. Metab. 93: 2194-2201, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18381570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18381570</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18381570[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2007-2825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18381570">Leboeuf et al. (2008)</a> investigated whether sensitivity to MEK inhibition was determined by oncogene status in 13 human thyroid cancer cell lines: 4 with mutation in BRAF, 4 with mutation in RAS, 1 carrying RET/PTC1 (see <a href="/entry/601985">601985</a>), and 4 wildtype. Thyroid cancers with BRAF mutation were preferentially sensitive to MEK inhibitors, whereas tumors with other MEK-ERK effector pathway gene mutations had variable responses, either because they were only partially dependent on ERK and/or because feedback responses elicited partial refractoriness to MEK inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18381570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#64" class="mim-tip-reference" title="Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M., Rosen, N. <strong>RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF.</strong> Nature 464: 427-430, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20179705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20179705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20179705[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20179705">Poulikakos et al. (2010)</a> used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for the paradoxical activation of the enzyme by inhibitors. Induction of ERK signaling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF-CRAF) or heterodimers (CRAF-BRAF) inhibits one promoter, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumors, RAS is not activated, thus transactivation is minimal and ERK signaling is inhibited in cells exposed to RAF inhibitors. These results indicated that RAF inhibitors will be effective in tumors in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signaling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumor activity than MEK inhibitors, but could also cause toxicity due to the MEK/ERK activation. <a href="#64" class="mim-tip-reference" title="Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M., Rosen, N. <strong>RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF.</strong> Nature 464: 427-430, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20179705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20179705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20179705[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20179705">Poulikakos et al. (2010)</a> noted that these predictions were borne out in a clinical trial of the RAF inhibitor PLX4032, as reported by <a href="#6" class="mim-tip-reference" title="Chapman, P., Puzanov, I., sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R., Grippo, J., Nolop, K., Flaherty, K. <strong>Early efficacy signal demonstrated in advanced melanoma in a phase I trial of the oncogenic BRAF-selective inhibitor PLX4032. (Abstract)</strong> Europ. J. Cancer Suppl. 7: 5 only, 2009."None>Chapman et al. (2009)</a> and <a href="#18" class="mim-tip-reference" title="Flaherty, K., Puzanov, I., Sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R. J., Grippo, J. F., Nolop, K., Chapman, P. <strong>Phase I study of PLX4032: proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. (Abstract-9000)</strong> J. Clin. Oncol. 27 (suppl.): 15s, 2009."None>Flaherty et al. (2009)</a>. The model indicated that promotion of RAF dimerization by elevation of wildtype RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumors. In agreement with this prediction, RAF inhibitors do not inhibit ERK signaling in cells that coexpress BRAF(V600E) and mutant RAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20179705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., Ludlam, M. J. C., Stokoe, D., Gloor, S. L., Vigers, G., Morales, T., Aliagas, I., and 9 others. <strong>RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.</strong> Nature 464: 431-435, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20130576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20130576</a>] [<a href="https://doi.org/10.1038/nature08833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20130576">Hatzivassiliou et al. (2010)</a> demonstrated that ATP-competitive RAF inhibitors have 2 opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumors, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signaling pathway and decrease tumor growth. Notably, in KRAS mutant and RAS/RAF wildtype tumors, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumor growth in some xenograft models. Inhibitor binding activates wildtype RAF isoforms by inducing dimerization, membrane localization, and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, <a href="#23" class="mim-tip-reference" title="Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., Ludlam, M. J. C., Stokoe, D., Gloor, S. L., Vigers, G., Morales, T., Aliagas, I., and 9 others. <strong>RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.</strong> Nature 464: 431-435, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20130576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20130576</a>] [<a href="https://doi.org/10.1038/nature08833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20130576">Hatzivassiliou et al. (2010)</a> demonstrated that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signaling pathways, depending on the cellular context. The authors stated that their work provided new insights into the therapeutic use of ATP-competitive RAF inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20130576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#59" class="mim-tip-reference" title="Park, E., Rawson, S., Li, K., Kim, B.-W., Ficarro, S. B., Gonzalez-Del Pino, G., Sharif, H., Marto, J. A., Jeon, H., Eck, M. J. <strong>Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes.</strong> Nature 575: 545-550, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31581174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31581174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31581174[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1660-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31581174">Park et al. (2019)</a> used cryoelectron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 (<a href="/entry/176872">176872</a>) and a 14-3-3 dimer of eta (YWHAH; <a href="/entry/113508">113508</a>) and zeta (YWHAZ; <a href="/entry/601288">601288</a>). The reconstruction revealed an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of 2 BRAFs, which drives the formation of an active, back-to-back BRAF dimer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31581174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#17" class="mim-tip-reference" title="Eychene, A., Barnier, J. V., Apiou, F., Dutrillaux, B., Calothy, G. <strong>Chromosomal assignment of two human B-raf(Rmil) proto-oncogene loci: B-raf-1 encoding the p94(Braf/Rmil) and B-raf-2, a processed pseudogene.</strong> Oncogene 7: 1657-1660, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1630826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1630826</a>]" pmid="1630826">Eychene et al. (1992)</a> identified 2 human BRAF loci: BRAF1, which was mapped to 7q34 by fluorescence in situ hybridization and shown to encode the functional gene product, and BRAF2, an inactive processed pseudogene located on Xq13. <a href="#76" class="mim-tip-reference" title="Sithanandam, G., Druck, T., Cannizzaro, L. A., Leuzzi, G., Huebner, K., Rapp, U. R. <strong>B-raf and a B-raf pseudogene are located on 7q in man.</strong> Oncogene 7: 795-799, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1565476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1565476</a>]" pmid="1565476">Sithanandam et al. (1992)</a> mapped the BRAF gene to the same region by Southern blot analysis of rodent/human somatic cell hybrids and by in situ hybridization, but concluded that the pseudogene is located near the active gene. Using a single interspecific backcross, <a href="#32" class="mim-tip-reference" title="Justice, M. J., Siracusa, L. D., Gilbert, D. J., Heisterkamp, N., Groffen, J., Chada, K., Silan, C. M., Copeland, N. G., Jenkins, N. A. <strong>A genetic linkage map of mouse chromosome 10: localization of eighteen molecular markers using a single interspecific backcross.</strong> Genetics 125: 855-866, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1975791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1975791</a>] [<a href="https://doi.org/10.1093/genetics/125.4.855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1975791">Justice et al. (1990)</a> demonstrated that the mouse Braf gene is located on chromosome 10. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1975791+1630826+1565476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#96" class="mim-tip-reference" title="Yuasa, Y., Kamiyama, T., Kato, M., Iwama, T., Ikeuchi, T., Tonomura, A. <strong>Transforming genes from familial adenomatous polyposis patient cells detected by a tumorigenicity assay.</strong> Oncogene 5: 589-596, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1970154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1970154</a>]" pmid="1970154">Yuasa et al. (1990)</a> searched for oncogenes associated with familial adenomatous polyposis by a tumorigenicity assay in nude mice. In the course of these studies, a transforming sequence was isolated that did not hybridize with 12 known oncogene probes. It was partially cloned and shown to be located on human chromosome 7. The gene did not hybridize with the MET (<a href="/entry/164860">164860</a>) and ERBB1 (<a href="/entry/131550">131550</a>) oncogenes which are located on chromosome 7. By sequence analysis of cDNA clones presumably containing the transforming gene, <a href="#33" class="mim-tip-reference" title="Kamiyama, T., Aoki, N., Yuasa, Y. <strong>B-raf oncogene: activation by rearrangements and assignment to human chromosome 7.</strong> Jpn. J. Cancer Res. 84: 250-256, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8098025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8098025</a>] [<a href="https://doi.org/10.1111/j.1349-7006.1993.tb02864.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8098025">Kamiyama et al. (1993)</a> showed that the sequence contained an activated BRAF, the 5-prime half of which was replaced by the SNRPE gene and an unknown gene. Analysis indicated that rearrangements had occurred during transfection. By Southern blot analysis of rodent-human somatic cell hybrid analysis, <a href="#33" class="mim-tip-reference" title="Kamiyama, T., Aoki, N., Yuasa, Y. <strong>B-raf oncogene: activation by rearrangements and assignment to human chromosome 7.</strong> Jpn. J. Cancer Res. 84: 250-256, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8098025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8098025</a>] [<a href="https://doi.org/10.1111/j.1349-7006.1993.tb02864.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8098025">Kamiyama et al. (1993)</a> mapped the BRAF gene to chromosome 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1970154+8098025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#10" class="mim-tip-reference" title="Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., Davis, N., Dicks, E., and 40 others. <strong>Mutations of the BRAF gene in human cancer.</strong> Nature 417: 949-954, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12068308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12068308</a>] [<a href="https://doi.org/10.1038/nature00766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12068308">Davies et al. (2002)</a> identified BRAF somatic missense mutations in 66% of malignant melanomas (see <a href="/entry/155600">155600</a>) and at lower frequency in a wide range of human cancers. All mutations were within the kinase domain, with a single substitution, V600E (<a href="#0001">164757.0001</a>), originally reported as V599E, accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH 3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V600E mutation. <a href="#10" class="mim-tip-reference" title="Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., Davis, N., Dicks, E., and 40 others. <strong>Mutations of the BRAF gene in human cancer.</strong> Nature 417: 949-954, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12068308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12068308</a>] [<a href="https://doi.org/10.1038/nature00766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12068308">Davies et al. (2002)</a> suggested that since BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma. Presumptive BRAF mutations were identified in 43 cancer cell lines including 20 of 34 (59%) melanomas, 7 of 40 (18%) colorectal cancers, 4 of 38 (11%) gliomas, 4 of 131 (3%) lung cancers, 5 of 59 (9%) sarcomas, 1 of 26 (4%) ovarian carcinomas, 1 of 45 (2%) breast cancers, and 1 of 7 (14%) liver cancers. Mutations were not found in cancer cell lines derived from 29 neuroblastomas, 10 bladder cancers, 53 leukemia/lymphomas, 11 cervical carcinomas, 11 renal cell carcinomas, 3 pancreatic carcinomas, 3 prostate carcinomas, 6 gastric carcinomas, 7 testicular carcinomas, 3 uterine carcinomas, and 29 other cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12068308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#67" class="mim-tip-reference" title="Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. <strong>RAF/RAS oncogenes and mismatch-repair status. (Letter)</strong> Nature 418: 934 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198537</a>] [<a href="https://doi.org/10.1038/418934a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198537">Rajagopalan et al. (2002)</a> systematically evaluated mutation in BRAF and KRAS (<a href="/entry/190070">190070</a>) in 330 colorectal tumors (see <a href="/entry/114500">114500</a>). There were 32 mutations in BRAF, 28 with a V600E mutation and 1 each with the R462I (<a href="#0002">164757.0002</a>), I463S (<a href="#0003">164757.0003</a>), G464E (<a href="#0004">164757.0004</a>), or K601E (<a href="#0005">164757.0005</a>) mutations. All but 2 mutations seemed to be heterozygous, and in all 20 cases for which normal tissue was available, the mutations were shown to be somatic. In the same set of tumors there were 169 mutations in KRAS. No tumor exhibited mutations in both BRAF and KRAS. There was also a striking difference in the frequency of BRAF mutations between cancers with and without mismatch repair deficiency. The V600E mutation was identified in all but 1 of the 15 mismatch repair deficient cases. <a href="#67" class="mim-tip-reference" title="Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. <strong>RAF/RAS oncogenes and mismatch-repair status. (Letter)</strong> Nature 418: 934 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198537</a>] [<a href="https://doi.org/10.1038/418934a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198537">Rajagopalan et al. (2002)</a> concluded their results provide strong support for the hypothesis that BRAF and KRAS mutations are equivalent in their tumorigenic effects. Both genes seem to be mutated at a similar phase of tumorigenesis, after initiation but before malignant conversion. Moreover, no tumor concurrently contained both BRAF and KRAS mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12198537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Kim, I.-J., Park, J.-H., Kang, H. C., Shin, Y., Park, H.-W., Park, H.-R., Ku, J.-L., Lim, S.-B., Park, J.-G. <strong>Mutational analysis of BRAF and K-ras in gastric cancers: absence of BRAF mutations in gastric cancers.</strong> Hum. Genet. 114: 118-120, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14513361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14513361</a>] [<a href="https://doi.org/10.1007/s00439-003-1027-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14513361">Kim et al. (2003)</a> stated that the most common BRAF mutation, V600E, had not been identified in tumors with mutations in the KRAS gene. They studied the incidence of BRAF mutations in gastric cancers and the relationship between BRAF and KRAS mutations in these cancers. They found 7 KRAS missense mutations in 66 gastric cancers and 16 gastric cancer cell lines. No BRAF mutations were found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14513361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#53" class="mim-tip-reference" title="Namba, H., Nakashima, M., Hayashi, T., Hayashida, N., Maeda, S., Rogounovitch, T. I., Ohtsuru, A., Saenko, V. A., Kanematsu, T., Yamashita, S. <strong>Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers.</strong> J. Clin. Endocr. Metab. 88: 4393-4397, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12970315/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12970315</a>] [<a href="https://doi.org/10.1210/jc.2003-030305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12970315">Namba et al. (2003)</a> determined the frequency of BRAF mutations in thyroid cancer and their correlation with clinicopathologic parameters. The V600E mutation was found in 4 of 6 cell lines and 51 of 207 thyroid tumors (24.6%). Examination of 126 patients with papillary thyroid cancer showed that BRAF mutation correlated significantly with distant metastasis (P = 0.033) and clinical stage (P = 0.049). The authors concluded that activating mutation in the BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12970315" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Giannini, R., Ugolini, C., Lupi, C., Proietti, A., Elisei, R., Salvatore, G., Berti, P., Materazzi, G., Miccoli, P., Santoro, M., Basolo, F. <strong>The heterozygous distribution of BRAF mutation supports the independent clonal origin of distinct tumor foci in multifocal papillary thyroid carcinoma.</strong> J. Clin. Endocr. Metab. 92: 3511-3516, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17535994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17535994</a>] [<a href="https://doi.org/10.1210/jc.2007-0594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17535994">Giannini et al. (2007)</a> examined the pattern of BRAF mutations in noncontiguous tumor foci and node metastases from 69 patients affected by multicentric PTC. Discordant patterns of BRAF mutation were found in about 40% of the multifocal PTCs. In node metastases, BRAF mutations were, in most but not all the cases, concordant with the dominant tumor. A discordant pattern of BRAF mutation was also found in about 50% of the cases in which multiple foci of different histopathologic variants were present. <a href="#22" class="mim-tip-reference" title="Giannini, R., Ugolini, C., Lupi, C., Proietti, A., Elisei, R., Salvatore, G., Berti, P., Materazzi, G., Miccoli, P., Santoro, M., Basolo, F. <strong>The heterozygous distribution of BRAF mutation supports the independent clonal origin of distinct tumor foci in multifocal papillary thyroid carcinoma.</strong> J. Clin. Endocr. Metab. 92: 3511-3516, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17535994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17535994</a>] [<a href="https://doi.org/10.1210/jc.2007-0594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17535994">Giannini et al. (2007)</a> concluded that the heterogeneous distribution of BRAF mutations suggests that discrete tumor foci in multifocal PTC may occur as independent tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17535994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Brose, M. S., Volpe, P., Feldman, M., Kumar, M., Rishi, I., Gerrero, R., Einhorn, E., Herlyn, M., Minna, J., Nicholson, A., Roth, J. A., Albelda, S. M., Davies, H., Cox, C., Brignell, G., Stephens, P., Futreal, P. A., Wooster, R., Stratton, M. R., Weber, B. L. <strong>BRAF and RAS mutations in human lung cancer and melanoma.</strong> Cancer Res. 62: 6997-7000, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12460918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12460918</a>]" pmid="12460918">Brose et al. (2002)</a> identified BRAF mutations in 5 of 179 nonsmall cell lung cancers (NSCLCs) and in 22 of 35 melanomas. Although more than 90% of previously identified BRAF mutations in melanoma involved codon 599, 8 of 9 in NSCLC were non-V600, strongly suggesting that BRAF mutations in NSCLC are qualitatively different from those in melanoma; thus, there may be therapeutic differences between lung cancer and melanoma in response to RAF inhibitors. Although uncommon, BRAF mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12460918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The discovery of activating mutations in the BRAF gene in many cutaneous melanomas prompted <a href="#14" class="mim-tip-reference" title="Edmunds, S. C., Cree, I. A., Di Nicolantonio, F., Hungerford, J. L., Hurren, J. S., Kelsell, D. P. <strong>Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas.</strong> Brit. J. Cancer 88: 1403-1405, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12778069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12778069</a>] [<a href="https://doi.org/10.1038/sj.bjc.6600919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12778069">Edmunds et al. (2003)</a> to screen the genomic sequence of BRAF exons 11 and 15 in a series of 48 intraocular (uveal) melanomas (<a href="/entry/155720">155720</a>), together with control samples from 3 cutaneous melanomas and a melanoma cell line that has a BRAF mutation. The same mutation was detected in two-thirds of the cutaneous samples, but was not present in any uveal melanomas. The finding further underlined the distinction between uveal and cutaneous melanomas, and suggested that BRAF inhibitors are unlikely to benefit patients with uveal melanoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12778069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using the very sensitive pyrophosphorolysis-activated polymerization (PAP) assay to screen for mutations in exon 15 of the BRAF gene in 11 uveal melanoma cell lines and 45 primary uveal melanomas, <a href="#48" class="mim-tip-reference" title="Maat, W., Kilic, E., Luyten, G. P. M., de Klein, A., Jager, M. J., Gruis, N. A., Van der Velden, P. A. <strong>Pyrophosphorolysis detects B-RAF mutations in primary uveal melanoma.</strong> Invest. Ophthal. Vis. Sci. 49: 23-27, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18172070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18172070</a>] [<a href="https://doi.org/10.1167/iovs.07-0722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18172070">Maat et al. (2008)</a> identified mutations in 2 cell lines (V600E; <a href="#0001">164757.0001</a>) and 6 primary tumors. Direct sequencing of the exon 15 PCR product did not reveal the mutations found with the PAP assay, indicating a low frequency of the mutant allele in primary samples. <a href="#48" class="mim-tip-reference" title="Maat, W., Kilic, E., Luyten, G. P. M., de Klein, A., Jager, M. J., Gruis, N. A., Van der Velden, P. A. <strong>Pyrophosphorolysis detects B-RAF mutations in primary uveal melanoma.</strong> Invest. Ophthal. Vis. Sci. 49: 23-27, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18172070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18172070</a>] [<a href="https://doi.org/10.1167/iovs.07-0722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18172070">Maat et al. (2008)</a> concluded that the relative scarcity of the BRAF mutations excluded an elemental role for them in uveal melanoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18172070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#88" class="mim-tip-reference" title="Wan, P. T. C., Garnett, M. J., Roe, S. M., Lee, S., Niculescu-Duvaz, D., Good, V. M., Cancer Genome Project, Jone, C. M., Marshall, C. J., Springer, C. J., Barford, D., Marais, R. <strong>Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.</strong> Cell 116: 855-867, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15035987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15035987</a>] [<a href="https://doi.org/10.1016/s0092-8674(04)00215-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15035987">Wan et al. (2004)</a> analyzed 22 BRAF mutants and found that 18 had elevated kinase activity and signaled to ERK (see <a href="/entry/601795">601795</a>) in vivo. Three mutants had reduced kinase activity towards MEK (see <a href="/entry/176872">176872</a>) in vitro but, by activating CRAF (<a href="/entry/164760">164760</a>) in vivo, signaled to ERK in cells. The structures of wildtype and oncogenic V600E mutant BRAF kinase domains in complex with a RAF inhibitor showed that the activation segment is held in an inactive conformation by association with the P loop. The authors stated that the clustering of most mutations to these 2 regions suggests that disruption of this interaction converts BRAF into its active conformation. The high-activity mutants signaled to ERK by directly phosphorylating MEK, whereas the impaired-activity mutants stimulated MEK by activating endogenous CRAF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15035987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Ciampi, R., Knauf, J. A., Kerler, R., Gandhi, M., Zhu, Z., Nikiforova, M. N., Rabes, H. M., Fagin, J. A., Nikiforov, Y. E. <strong>Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer.</strong> J. Clin. Invest. 115: 94-101, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15630448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15630448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15630448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI23237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15630448">Ciampi et al. (2005)</a> reported a rearrangement of BRAF via paracentric inversion of chromosome 7q, resulting in an in-frame fusion between exons 1-8 of the AKAP9 gene (<a href="/entry/604001">604001</a>) and exons 9-18 of BRAF. The fusion protein contained the protein kinase domain and lacked the autoinhibitory N-terminal portion of BRAF. It had elevated kinase activity and transformed NIH 3T3 cells. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas developing after a short latency, whereas BRAF point mutations (see <a href="#0001">164757.0001</a>) were absent in this group. <a href="#7" class="mim-tip-reference" title="Ciampi, R., Knauf, J. A., Kerler, R., Gandhi, M., Zhu, Z., Nikiforova, M. N., Rabes, H. M., Fagin, J. A., Nikiforov, Y. E. <strong>Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer.</strong> J. Clin. Invest. 115: 94-101, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15630448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15630448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15630448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI23237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15630448">Ciampi et al. (2005)</a> concluded that in thyroid cancer, radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions, whereas in sporadic forms of the disease, effectors along the same pathway are activated predominantly by point mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15630448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Oncogenic mutations in the DNA sequence encoding the kinase domain of BRAF are found in most primary cell lines derived from cutaneous melanomas (<a href="#10" class="mim-tip-reference" title="Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., Davis, N., Dicks, E., and 40 others. <strong>Mutations of the BRAF gene in human cancer.</strong> Nature 417: 949-954, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12068308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12068308</a>] [<a href="https://doi.org/10.1038/nature00766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12068308">Davies et al., 2002</a>; <a href="#5" class="mim-tip-reference" title="Brose, M. S., Volpe, P., Feldman, M., Kumar, M., Rishi, I., Gerrero, R., Einhorn, E., Herlyn, M., Minna, J., Nicholson, A., Roth, J. A., Albelda, S. M., Davies, H., Cox, C., Brignell, G., Stephens, P., Futreal, P. A., Wooster, R., Stratton, M. R., Weber, B. L. <strong>BRAF and RAS mutations in human lung cancer and melanoma.</strong> Cancer Res. 62: 6997-7000, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12460918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12460918</a>]" pmid="12460918">Brose et al., 2002</a>). Approximately 90% of these mutations in melanomas are due to a recurrent 1799T-A transversion in exon 15 of the BRAF gene, resulting in a V600E mutation (<a href="#0001">164757.0001</a>), suggesting that a specific environmental exposure contributes to the genesis of this mutation; however, the common 1799T-A BRAF mutation is not a characteristic ultraviolet signature mutation. <a href="#15" class="mim-tip-reference" title="Edwards, R. H., Ward, M. R., Wu, H., Medina, C. A., Brose, M. S., Volpe, P., Nussen-Lee, S., Haupt, H. M., Martin, A. M., Herlyn, M., Lessin, S. R., Weber, B. L. <strong>Absence of BRAF mutations in UV-protected mucosal melanomas.</strong> J. Med. Genet. 41: 270-272, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15060100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15060100</a>] [<a href="https://doi.org/10.1136/jmg.2003.016667" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15060100">Edwards et al. (2004)</a> studied the BRAF gene in melanomas arising in sites protected from sun exposure. None of 13 mucosal melanomas had a mutation in exon 15 of the BRAF gene, as compared to 54 of 165 (33%) primary cutaneous melanomas in a compilation of all previously published studies. The data suggested that UV exposure plays a role in the genesis of BRAF mutations in cutaneous melanomas, despite the absence of the characteristic C-to-T or CC-to-TT mutation signature associated with UV exposure, and suggested mechanisms other than pyrimidine dimer formation as important in UV-induced mutagenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12068308+12460918+15060100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Landi, M. T., Bauer, J., Pfeiffer, R. M., Elder, D. E., Hulley, B., Minghetti, P., Calista, D., Kanetsky, P. A., Pinkel, D., Bastian, B. C. <strong>MC1R germline variants confer risk for BRAF-mutant melanoma.</strong> Science 313: 521-522, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16809487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16809487</a>] [<a href="https://doi.org/10.1126/science.1127515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16809487">Landi et al. (2006)</a> showed that MC1R (<a href="/entry/155555">155555</a>) variants are strongly associated with BRAF mutations in nonchronic sun-induced damage melanomas. In this tumor subtype, the risk for melanoma associated with MC1R is due to an increase in risk of developing melanomas with BRAF mutations. <a href="#41" class="mim-tip-reference" title="Landi, M. T., Bauer, J., Pfeiffer, R. M., Elder, D. E., Hulley, B., Minghetti, P., Calista, D., Kanetsky, P. A., Pinkel, D., Bastian, B. C. <strong>MC1R germline variants confer risk for BRAF-mutant melanoma.</strong> Science 313: 521-522, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16809487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16809487</a>] [<a href="https://doi.org/10.1126/science.1127515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16809487">Landi et al. (2006)</a> found that BRAF mutations were more frequent in nonchronic sun-induced damage melanoma cases with germline MC1R variants than in those with 2 wildtype MC1R alleles. When the authors categorized patients into 2 groups, homozygous MC1R wildtype versus all others, they found that BRAF mutations were 6 to 13 times as frequent in those with at least 1 MC1R variant allele compared to those with no MC1R variants. Four more tests for interaction between age and MC1R were not significant. Comparison of nonchronic sun-damaged Italian cases with 171 healthy Italian controls showed that the overall melanoma risk was higher by a factor of 3.3 (95% CI 1.5-6.9) in individuals with any MC1R variant allele compared to individuals with no variant alleles and that the risk increased with the number of variant MC1R alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16809487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Desmoplastic melanoma is an uncommon variant of cutaneous melanoma that mimics soft tissue sarcoma both clinically and morphologically. An activating point mutation in the BRAF oncogene has been identified in a high proportion of conventional cutaneous melanomas, but <a href="#11" class="mim-tip-reference" title="Davison, J. M., Rosenbaum, E., Barrett, T. L., Goldenberg, D., Hoque, M. O., Sidransky, D., Westra, W. H. <strong>Absence of V599E BRAF mutations in desmoplastic melanomas.</strong> Cancer 103: 788-792, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15641040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15641040</a>] [<a href="https://doi.org/10.1002/cncr.20861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15641040">Davison et al. (2005)</a> showed that the desmoplastic variant frequency does not harbor such a mutation. Accordingly, patients with melanomas should not be collectively regarded as a uniform group as new therapeutic strategies are developed that target specific genetic alterations. They found the V600E mutation in 23 of 57 conventional cutaneous melanoma specimens but in none of 12 desmoplastic melanoma specimens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15641040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., Peeper, D. S. <strong>BRAF(E600)-associated senescence-like cell cycle arrest of human naevi. (Letter)</strong> Nature 436: 720-724, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16079850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16079850</a>] [<a href="https://doi.org/10.1038/nature03890" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16079850">Michaloglou et al. (2005)</a> showed that sustained expression of BRAF carrying the V600E mutation (<a href="#0001">164757.0001</a>) in human melanocytes induced cell cycle arrest, which was accompanied by the induction of both p16(INK4A) (<a href="/entry/600160">600160</a>) and senescence-associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital nevi were invariably positive for SA-beta-Gal expression, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, <a href="#52" class="mim-tip-reference" title="Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., Peeper, D. S. <strong>BRAF(E600)-associated senescence-like cell cycle arrest of human naevi. (Letter)</strong> Nature 436: 720-724, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16079850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16079850</a>] [<a href="https://doi.org/10.1038/nature03890" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16079850">Michaloglou et al. (2005)</a> observed a marked mosaic induction of p16(INK4a), suggesting that factors other than p16(INK4a) contribute to protection against BRAF(V600E)-driven proliferation. Nevi did not appear to suffer from telomere attrition, arguing in favor of an active oncogene-driven senescence process rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAF(V600E)-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiologic process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16079850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#79" class="mim-tip-reference" title="Sommerer, F., Hengge, U. R., Markwarth, A., Vomschloss, S., Stolzenburg, J.-U., Wittekind, C., Tannapfel, A. <strong>Mutations of BRAF and RAS are rare events in germ cell tumours.</strong> Int. J. Cancer 113: 329-335, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15386408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15386408</a>] [<a href="https://doi.org/10.1002/ijc.20567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15386408">Sommerer et al. (2005)</a> analyzed the BRAF gene in 30 seminomas and 32 nonseminomatous GCTs (see <a href="/entry/273300">273300</a>) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma. The activating BRAF missense mutation 1796T-A (V600E; <a href="#0001">164757.0001</a>) was identified in 3 (9%) of 32 nonseminomatous tumors, within the embryonic carcinoma component; no BRAF mutations were found in the seminomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15386408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Curtin, J. A., Fridlyand, J., Kageshita, T., Patel, H. N., Busam, K. J., Kutzner, H., Cho, K.-H., Aiba, S., Brocker, E.-B., LeBoit, P. E., Pinkel, D., Bastian, B. C. <strong>Distinct sets of genetic alterations in melanoma.</strong> New Eng. J. Med. 353: 2135-2147, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16291983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16291983</a>] [<a href="https://doi.org/10.1056/NEJMoa050092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16291983">Curtin et al. (2005)</a> demonstrated genetic diversity in melanomas related to susceptibility to ultraviolet light. They compared genomewide alternations in DNA copy number and mutation status of BRAF and NRAS (<a href="/entry/164790">164790</a>) in 126 melanomas from 4 clinical groups in which the degree of exposure to ultraviolet light differed: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from arms, soles, and subungual (acral) sites; and 20 mucosal melanomas. They found significant differences in the frequencies of regional changes in DNA copy number and the frequencies of mutations in BRAF among the 4 groups of melanomas. These samples could be correctly classified into the 4 groups with 70% accuracy on the basis of changes in the number of copies of genomic DNA. In 2-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84% accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89% accuracy. In 81% of melanomas on skin without chronic sun-induced damage, they found mutations in BRAF or NRAS; most melanomas in the other groups had mutations in neither gene. Melanomas with wildtype BRAF or NRAS frequently had increases in the number of copies of genes for cyclin-dependent kinase-4 (CDK4; <a href="/entry/123829">123829</a>) and cyclin-1 (CCND1; <a href="/entry/168461">168461</a>), which are downstream components of the RAS-BRAF pathway. In these studies, alterations in the number of copies of DNA was determined by comparative genomic hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16291983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#50" class="mim-tip-reference" title="Meltzer, P. S. <strong>Genetic diversity in melanoma.</strong> New Eng. J. Med. 353: 2104-2107, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16291979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16291979</a>] [<a href="https://doi.org/10.1056/NEJMp058173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16291979">Meltzer (2005)</a> commented that information of the type provided by <a href="#8" class="mim-tip-reference" title="Curtin, J. A., Fridlyand, J., Kageshita, T., Patel, H. N., Busam, K. J., Kutzner, H., Cho, K.-H., Aiba, S., Brocker, E.-B., LeBoit, P. E., Pinkel, D., Bastian, B. C. <strong>Distinct sets of genetic alterations in melanoma.</strong> New Eng. J. Med. 353: 2135-2147, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16291983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16291983</a>] [<a href="https://doi.org/10.1056/NEJMoa050092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16291983">Curtin et al. (2005)</a> will become increasingly important to the management of melanoma, and that a strong case can be made for monitoring BRAF mutation status in clinical trials of BRAF antagonists. Because BRAF mutations are uncommon in certain subgroups of patients, these groups may require uniquely tailored therapies. Clues from the gain of oncogenes identified by array-based comparative genomic hybridization may help identify new drug targets. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16291979+16291983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Aberrant DNA methylation of CpG islands has been extensively observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype,' or 'CIMP' (<a href="#83" class="mim-tip-reference" title="Toyota, M., Ahuja, N., Ohe-Toyota, M., Herman, J. G., Baylin, S. B., Issa, J.-P. J. <strong>CpG island methylator phenotype in colorectal cancer.</strong> Proc. Nat. Acad. Sci. 96: 8681-8686, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10411935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10411935</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10411935[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.15.8681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10411935">Toyota et al., 1999</a>; <a href="#27" class="mim-tip-reference" title="Issa, J.-P. <strong>CpG island methylator phenotype in cancer.</strong> Nature Rev. Cancer 4: 988-993, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15573120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15573120</a>] [<a href="https://doi.org/10.1038/nrc1507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15573120">Issa, 2004</a>). However, the existence of CIMP has been challenged. To resolve this controversy, <a href="#89" class="mim-tip-reference" title="Weisenberger, D. J., Siegmund, K. D., Campan, M., Young, J., Long, T. I., Faasse, M. A., Kang, G. H., Widschwendter, M., Weener, D., Buchanan, D., Koh, H., Simms, L., and 9 others. <strong>CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.</strong> Nature Genet. 38: 787-793, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804544</a>] [<a href="https://doi.org/10.1038/ng1834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804544">Weisenberger et al. (2006)</a> conducted a systematic, stepwise screen of 195 CpG island methylation markers involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. They found that CIMP-positive tumors convincingly represented a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occurred almost exclusively as a consequence of CIMP-associated methylation of MLH1 (<a href="/entry/120436">120436</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15573120+16804544+10411935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a pilocytic astrocytoma (see <a href="/entry/137800">137800</a>), <a href="#31" class="mim-tip-reference" title="Jones, D. T. W., Kocialkowski, S., Liu, L., Pearson, D. M., Ichimura, K., Collins, V. P. <strong>Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma.</strong> Oncogene 28: 2119-2123, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19363522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19363522</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19363522[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/onc.2009.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19363522">Jones et al. (2009)</a> identified a somatic 3-bp insertion at either nucleotide 1795 or 1796 within codon 598 of the BRAF gene. The mutation resulted in the introduction of an additional threonine near the mutational hotspot V600 and produced a constitutively active BRAF that induced anchorage-independent growth in mouse fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19363522" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#95" class="mim-tip-reference" title="Yu, J., Deshmukh, H., Gutmann, R. J., Emnett, R. J., Rodriguez, F. J., Watson, M. A., Nagarajan, R., Gutmann, D. H. <strong>Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma.</strong> Neurology 73: 1526-1531, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19794125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19794125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19794125[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c0664a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19794125">Yu et al. (2009)</a> found that 42 (60%) of 70 sporadic pilocytic astrocytomas had rearrangements of the BRAF gene. Two additional tumors with no rearrangement carried a BRAF mutation. Twenty-two of 36 tumors with BRAF rearrangements had corresponding amplification of the neighboring HIPK2 gene (<a href="/entry/606868">606868</a>). However, 14 of 36 tumors with BRAF rearrangement had no detectable HIPK2 gene amplification. Six of 20 tumors demonstrated HIPK2 amplification without apparent BRAF rearrangement or mutation. Only 12 (17%) of the 70 tumors lacked detectable BRAF or HIPK2 alterations. <a href="#95" class="mim-tip-reference" title="Yu, J., Deshmukh, H., Gutmann, R. J., Emnett, R. J., Rodriguez, F. J., Watson, M. A., Nagarajan, R., Gutmann, D. H. <strong>Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma.</strong> Neurology 73: 1526-1531, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19794125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19794125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19794125[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c0664a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19794125">Yu et al. (2009)</a> concluded that BRAF rearrangement represents the most common genetic alteration in sporadic pilocytic astrocytomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19794125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Gala, M. K., Mizukami, Y., Le, L. P., Moriichi, K., Austin, T., Yamamoto, M., Lauwers, G. Y., Bardeesy, N., Chung, D. C. <strong>Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.</strong> Gastroenterology 146: 520-529, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24512911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24512911</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24512911[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1053/j.gastro.2013.10.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24512911">Gala et al. (2014)</a> analyzed tissue from sessile serrated adenomas (SSAs) from 19 individuals with sessile serrated polyposis cancer syndrome (SSPCS; <a href="/entry/617108">617108</a>), and found that 18 of the genotyped SSAs carried the BRAF V600E mutation (<a href="#0001">164757.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24512911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#94" class="mim-tip-reference" title="Yao, Z., Yaeger, R., Rodrik-Outmezguine, V. S., Tao, A., Torres, N. M., Chang, M. T., Drosten, M., Zhao, H., Cecchi, F., Hembrough, T., Michels, J., Baumert, H., Miles, L., Campbell, N. M., de Stanchina, E., Solit, D. B., Barbacid, M., Taylor, B. S., Rosen, N. <strong>Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.</strong> Nature 548: 234-238, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28783719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28783719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28783719[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature23291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28783719">Yao et al. (2017)</a> summarized 2 classes of oncogenic BRAF mutants that determine their sensitivity to inhibitors and described a third class. Class 1 BRAF mutations (V600 mutations) are RAS-independent, signal as monomers, and are sensitive to RAF monomer inhibitors. Class 2 BRAF mutants are RAS-independent, signal as constitutive dimers, and are resistant to vemurafenib but may be sensitive to RAF dimer inhibitors or MEK inhibitors. The third class of BRAF mutants comprises those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signaling is RAS-dependent. The mutants bind more tightly than wildtype BRAF to RAS-GTP, and their binding to and activation of wildtype CRAF (<a href="/entry/164760">164760</a>) is enhanced, leading to increased ERK signaling. The model suggests that dysregulation of signaling by these mutants in tumors requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbor RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signaling. These tumors are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. <a href="#94" class="mim-tip-reference" title="Yao, Z., Yaeger, R., Rodrik-Outmezguine, V. S., Tao, A., Torres, N. M., Chang, M. T., Drosten, M., Zhao, H., Cecchi, F., Hembrough, T., Michels, J., Baumert, H., Miles, L., Campbell, N. M., de Stanchina, E., Solit, D. B., Barbacid, M., Taylor, B. S., Rosen, N. <strong>Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.</strong> Nature 548: 234-238, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28783719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28783719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28783719[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature23291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28783719">Yao et al. (2017)</a> concluded that the 3 distinct functional classes of BRAF mutants in human tumors activate ERK signaling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28783719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Nieto, P., Ambrogio, C., Esteban-Burgos, L., Gomez-Lopez, G., Blasco, M. T., Yao, Z., Marais, R., Rosen, N., Chiarle, R., Pisano, D. G., Barbacid, M., Santamaria, D. <strong>A Braf kinase-inactive mutant induces lung adenocarcinoma.</strong> Nature 548: 239-243, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28783725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28783725</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28783725[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature23297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28783725">Nieto et al. (2017)</a> showed that a kinase-inactive form of BRAF triggered lung adenocarcinoma in vivo in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28783725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Germline Mutations in Cardiofaciocutaneous Syndrome, Noonan Syndrome 7, and LEOPARD Syndrome 3</em></strong></p><p>
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Cardiofaciocutaneous (CFC) syndrome (see CFC1, <a href="/entry/115150">115150</a>) is characterized by a distinctive facial appearance, heart defects, and mental retardation. Phenotypically, CFC overlaps Noonan syndrome (see <a href="/entry/163950">163950</a>) and Costello syndrome (<a href="/entry/218040">218040</a>). The finding of HRAS (<a href="/entry/190020">190020</a>) mutations in individuals with Costello syndrome, and of PTPN11 (<a href="/entry/176876">176876</a>) mutations in individuals with Noonan syndrome, suggested to <a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> that activation of the RAS-MAPK pathway is the common underlying mechanism of Noonan syndrome and Costello syndrome, and, hence, possibly of CFC syndrome. <a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> sequenced the entire 18 coding exons of BRAF, an isoform in the RAF protooncogene family, in 40 individuals with CFC syndrome and identified 8 different mutations (e.g., <a href="#0012">164757.0012</a>) in 16 of the patients. They also found 2 mutations in the KRAS gene (<a href="/entry/190070#0009">190070.0009</a>, <a href="/entry/190070#0010">190070.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> compared manifestations between KRAS-positive (CFC2; <a href="/entry/615278">615278</a>) and BRAF-positive individuals with CFC and found similar frequencies of growth and mental retardation, craniofacial appearance, abnormal hair, and heart defects. However, there was a difference between the 2 groups in manifestations of skin abnormalities, including ichthyosis, hyperkeratosis, and hemangioma, which were observed in 13 BRAF-positive individuals but in no KRAS-positive individuals. Somatic mutations in BRAF were identified in 60% of malignant melanoma or nevi by <a href="#21" class="mim-tip-reference" title="Garnett, M. J., Marais, R. <strong>Guilty as charged: B-RAF is a human oncogene.</strong> Cancer Cell 6: 313-319, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15488754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15488754</a>] [<a href="https://doi.org/10.1016/j.ccr.2004.09.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15488754">Garnett and Marais (2004)</a>, suggesting that BRAF has an important role in the skin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16474404+15488754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A. <strong>Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.</strong> Science 311: 1287-1290, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16439621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16439621</a>] [<a href="https://doi.org/10.1126/science.1124642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16439621">Rodriguez-Viciana et al. (2006)</a> screened 23 CFC patients for mutations in BRAF. Eighteen of 23, or 78% of individuals, had mutations in BRAF; 11 distinct missense mutations clustered in 2 regions. Five individuals had a gln257-to-arg missense mutation (<a href="#0013">164757.0013</a>) in the cysteine-rich domain of the conserved region 1 (CR1). The other cluster of mutations was in the protein kinase domain and involved exons 11, 12, 14, and 15. Five patients had heterogeneous missense mutations in exon 12. All parents and controls, totaling 40 phenotypically unaffected individuals, had none of these mutations, supporting the hypothesis that occurrence of CFC is sporadic. <a href="#71" class="mim-tip-reference" title="Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A. <strong>Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.</strong> Science 311: 1287-1290, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16439621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16439621</a>] [<a href="https://doi.org/10.1126/science.1124642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16439621">Rodriguez-Viciana et al. (2006)</a> suggested that although the causative mutations in BRAF were heterogeneous, the distribution of mutations was specific and nonrandom. No frameshift, nonsense, or splice site mutations were detected in the cohort of patients; thus, BRAF haploinsufficiency is not a likely causative mechanism of CFC. Of the 5 individuals without BRAF mutation, 3 had mutation in either MEK1 (<a href="/entry/176872">176872</a>) or MEK2 (<a href="/entry/601263">601263</a>); the disease-causing mutation in the remaining 2 individuals was not identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16439621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients originally diagnosed with Costello syndrome but with features overlapping those of CFC, in whom no HRAS mutations were found (<a href="#16" class="mim-tip-reference" title="Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., Rauen, K. A. <strong>HRAS mutation in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.</strong> Am. J. Med. Genet. 140A: 8-16, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16372351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16372351</a>] [<a href="https://doi.org/10.1002/ajmg.a.31078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16372351">Estep et al., 2006</a>), <a href="#70" class="mim-tip-reference" title="Rauen, K. A. <strong>Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. (Letter)</strong> Am. J. Med. Genet. 140A: 1681-1683, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804887</a>] [<a href="https://doi.org/10.1002/ajmg.a.31315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804887">Rauen (2006)</a> identified missense mutations in the BRAF gene (<a href="#0020">164757.0020</a> and <a href="#0021">164757.0021</a>, respectively). The author noted that the mutations involved exons that were not previously described in CFC patients with BRAF mutations. <a href="#70" class="mim-tip-reference" title="Rauen, K. A. <strong>Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. (Letter)</strong> Am. J. Med. Genet. 140A: 1681-1683, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804887</a>] [<a href="https://doi.org/10.1002/ajmg.a.31315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804887">Rauen (2006)</a> stated that Costello syndrome and CFC can be distinguished by mutation analysis of genes in the RAS/MAPK pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16804887+16372351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#74" class="mim-tip-reference" title="Schulz, A. L., Albrecht, B., Arici, C., van der Burgt, I., Buske, A., Gillessen-Kaesbach, G., Heller, R., Horn, D., Hubner, C. A., Korenke, G. C., Konig, R., Kress, W., and 15 others. <strong>Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome</strong> Clin. Genet. 73: 62-70, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18042262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18042262</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00931.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18042262">Schulz et al. (2008)</a> identified 12 different mutations in the BRAF gene in 24 (47.0%) of 51 patients with cardiofaciocutaneous syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18042262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#73" class="mim-tip-reference" title="Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others. <strong>Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.</strong> Hum. Mutat. 30: 695-702, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19206169[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206169">Sarkozy et al. (2009)</a> identified heterozygous de novo mutations in the BRAF gene (see, e.g., <a href="#0022">164757.0022</a>, <a href="#0023">164757.0023</a>, <a href="#0025">164757.0025</a>, and <a href="#0026">164757.0026</a>) in 17 (52%) of 33 patients with CFC, 5 (1.9%) of 270 patients with Noonan syndrome (NS7; <a href="/entry/613706">613706</a>), and 1 (17%) of 6 patients with LEOPARD syndrome (LPRD3; <a href="/entry/613707">613707</a>). The mutations clustered in exon 6, encoding the cysteine-rich domain, and in exons 11 to 17, encoding the kinase domain, and did not overlap with cancer-causing BRAF mutations. In vitro functional expression studies of selected variants showed variable gain of function, but little or no transforming ability; all mutations had less activating potential than the common V600E mutation (<a href="#0001">164757.0001</a>). However, the CFC-associated mutations tended to have a slightly more activating ability compared to the NS7-and LEOPARD-associated mutations. <a href="#73" class="mim-tip-reference" title="Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others. <strong>Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.</strong> Hum. Mutat. 30: 695-702, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19206169[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206169">Sarkozy et al. (2009)</a> noted that none of the NS7-associated mutations were found in patients with CFC, suggesting that the phenotypes resulting from germline BRAF mutations may be allele-specific. Overall, the findings expanded the phenotypic spectrum associated with germline BRAF mutations, suggesting a spectrum of diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#30" class="mim-tip-reference" title="Jones, D. T. W., Kocialkowski, S., Liu, L., Pearson, D. M., Backlund, L. M., Ichimura, K., Collins, V. P. <strong>Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas.</strong> Cancer Res. 68: 8673-8677, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18974108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18974108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18974108[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-08-2097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18974108">Jones et al. (2008)</a> identified tandem duplications of about 2 Mb at chromosome 7q34 in 29 (66%) of 44 pilocytic astrocytomas (see <a href="/entry/137800">137800</a>). These rearrangements were not observed in 244 higher grade astrocytomas. The duplications resulted in 3 different in-frame fusion genes containing most 5-prime exons of the KIAA1549 gene (<a href="/entry/613344">613344</a>) and several 3-prime exons of the BRAF gene. The most common fusion was between KIAA1549 exon 16 and BRAF exon 9, which occurred in 20 pilocytic astrocytomas. All breakpoint variants were expected to encode functionally similar proteins containing the C-terminal kinase domain of BRAF without the N-terminal BRAF autoregulatory domain. Similar to wildtype KIAA1549, which produces a short variant through the use of an internal promoter, PCR analysis detected both long and short variants of the KIAA1549/BRAF fusion transcript. COS-7 cells transfected with either long or short KIAA1549/BRAF fusion transcripts showed constitutive BRAF kinase activity, and NIH3T3 cells transfected with the short KIAA1549/BRAF fusion transcript showed anchorage-independent growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18974108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#90" class="mim-tip-reference" title="Wojnowski, L., Zimmer, A. M., Beck, T. W., Hahn, H., Bernal, R., Rapp, U. R., Zimmer, A. <strong>Endothelial apoptosis in Braf-deficient mice.</strong> Nature Genet. 16: 293-297, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9207797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9207797</a>] [<a href="https://doi.org/10.1038/ng0797-293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9207797">Wojnowski et al. (1997)</a> showed that mice with a targeted disruption in the Braf gene die of vascular defects during midgestation. Homozygous deficient embryos, unlike those homozygous for deficiency of Araf (<a href="/entry/311010">311010</a>) or Craf1, showed an increased number of endothelial precursor cells, dramatically enlarged blood vessels, and apoptotic death of differentiated endothelial cells. These results established Braf as a critical signaling factor in the formation of the vascular system and provided the first genetic evidence for an essential role of a Raf gene in the regulation of programmed cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9207797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To build a model of human melanoma, <a href="#9" class="mim-tip-reference" title="Dankort, D., Curley, D. P., Cartlidge, R. A., Nelson, B., Karnezis, A. N., Damsky, W. E., Jr., You, M. J., DePinho, R. A., McMahon, M., Bosenberg, M. <strong>Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.</strong> Nature Genet. 41: 544-552, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19282848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19282848</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19282848[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19282848">Dankort et al. (2009)</a> generated mice with conditional melanocyte-specific expression of Braf(V600E) (<a href="#0001">164757.0001</a>). Upon induction of Braf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15 to 20 months. By contrast, expression of Braf(V600E) combined with Pten (<a href="/entry/601728">601728</a>) tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency, and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (see <a href="/entry/601231">601231</a>) or MEK1/2 (<a href="/entry/176872">176872</a>, <a href="/entry/601263">601263</a>) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with both drug inhibitors led to shrinkage of established melanomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19282848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Inoue, S., Moriya, M., Watanabe, Y., Miyagawa-Tomita, S., Niihori, T., Oba, D., Ono, M., Kure, S., Ogura, T., Matsubara, Y., Aoki, Y. <strong>New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome.</strong> Hum. Molec. Genet. 23: 6553-6566, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25035421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25035421</a>] [<a href="https://doi.org/10.1093/hmg/ddu376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25035421">Inoue et al. (2014)</a> created heterozygous knockin mice expressing Braf with a gln241-to-arg (Q241R) mutation, which corresponds to the most frequent mutation in CFC syndrome, gln257 to arg (Q257R; <a href="#0013">164757.0013</a>). Braf Q241R/+ mice showed embryonic or neonatal lethality, with liver necrosis, edema, craniofacial abnormalities, and heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction, and ventricular septal defects. Braf Q241R/+ embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels. Prenatal treatment with a Mek inhibitor partly rescued embryonic lethality in Braf Q241R/+ embryos, with amelioration of craniofacial abnormalities and edema. One surviving pup was obtained following treatment with a histone-3 demethylase inhibitor. Combined treatment with Mek and histone-3 demethylase inhibitors further increased the survival rate in Braf Q241R/+ embryos and ameliorated enlarged cardiac valves. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25035421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Inoue, S., Morozumi, N., Yoshikiyo, K., Maeda, H., Aoki, Y. <strong>C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome.</strong> Hum. Molec. Genet. 28: 74-83, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30239744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30239744</a>] [<a href="https://doi.org/10.1093/hmg/ddy333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30239744">Inoue et al. (2019)</a> found that Braf Q241R/+ mice had decreased body weight, body length, and growth plate width compared with wildtype mice. Immunohistochemical analysis showed activated Erk in hypertrophic chondrocytes from Braf Q241R/+ mice, leading to impaired growth plate chondrogenesis without affecting chondrocyte proliferation and apoptosis, resulting in postnatal growth retardation. In addition, serum Igf1 (<a href="/entry/147440">147440</a>) and Igfbp3 (<a href="/entry/146732">146732</a>) levels in Braf Q241R/+ mice were transiently decreased due to poor nutritional status. Treatment with C-type natriuretic peptide (CNP; <a href="/entry/600296">600296</a>), a stimulator of endochondral and long bone growth, increased body length and tail length in both Braf Q241R/+ and wildtype mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30239744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113488022 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113488022;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs113488022?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs113488022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs113488022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014992 OR RCV000014993 OR RCV000014994 OR RCV000022677 OR RCV000037936 OR RCV000067669 OR RCV000080903 OR RCV000208763 OR RCV000430562 OR RCV000443448 OR RCV000662278 OR RCV000860020 OR RCV001030023 OR RCV001248834 OR RCV001254874 OR RCV002051586 OR RCV003458334 OR RCV004018627 OR RCV004719648 OR RCV005089260" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014992, RCV000014993, RCV000014994, RCV000022677, RCV000037936, RCV000067669, RCV000080903, RCV000208763, RCV000430562, RCV000443448, RCV000662278, RCV000860020, RCV001030023, RCV001248834, RCV001254874, RCV002051586, RCV003458334, RCV004018627, RCV004719648, RCV005089260" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014992...</a>
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<p>The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). <a href="#40" class="mim-tip-reference" title="Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., Hemminki, K. <strong>BRAF mutations in metastatic melanoma: a possible association with clinical outcome.</strong> Clin. Cancer Res. 9: 3362-3368, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960123</a>]" pmid="12960123">Kumar et al. (2003)</a> noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12960123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Malignant Melanoma</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., Davis, N., Dicks, E., and 40 others. <strong>Mutations of the BRAF gene in human cancer.</strong> Nature 417: 949-954, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12068308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12068308</a>] [<a href="https://doi.org/10.1038/nature00766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12068308">Davies et al. (2002)</a> identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see <a href="/entry/155600">155600</a>). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12068308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To evaluate the timing of mutations in BRAF during melanocyte neoplasia, <a href="#61" class="mim-tip-reference" title="Pollock, P. M., Harper, U. L., Hansen, K. S., Yudt, L. M., Stark, M., Robbins, C. M., Moses, T. Y., Hostetter, G., Wagner, U., Kakareka, J., Salem, G., Pohida, T., Heenan, P., Duray, P., Kallioniemi, O., Hayward, N. K., Trent, J. M., Meltzer, P. S. <strong>High frequency of BRAF mutations in nevi.</strong> Nature Genet. 33: 19-20, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447372</a>] [<a href="https://doi.org/10.1038/ng1054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447372">Pollock et al. (2003)</a> carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Lang, J., Boxer, M., MacKie, R. <strong>Absence of exon 15 BRAF germline mutations in familial melanoma.</strong> Hum. Mutat. 21: 327-330, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12619120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12619120</a>] [<a href="https://doi.org/10.1002/humu.10188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12619120">Lang et al. (2003)</a> failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (<a href="/entry/600160">600160</a>). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. <a href="#51" class="mim-tip-reference" title="Meyer, P., Klaes, R., Schmitt, C., Boettger, M. B., Garbe, C. <strong>Exclusion of BRAF(V599E) as a melanoma susceptibility mutation.</strong> Int. J. Cancer 106: 78-80, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794760</a>] [<a href="https://doi.org/10.1002/ijc.11199" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12794760">Meyer et al. (2003)</a> found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12794760+12619120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Kim, I.-J., Park, J.-H., Kang, H. C., Shin, Y., Park, H.-W., Park, H.-R., Ku, J.-L., Lim, S.-B., Park, J.-G. <strong>Mutational analysis of BRAF and K-ras in gastric cancers: absence of BRAF mutations in gastric cancers.</strong> Hum. Genet. 114: 118-120, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14513361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14513361</a>] [<a href="https://doi.org/10.1007/s00439-003-1027-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14513361">Kim et al. (2003)</a> stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (<a href="/entry/190070">190070</a>). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (<a href="#67" class="mim-tip-reference" title="Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. <strong>RAF/RAS oncogenes and mismatch-repair status. (Letter)</strong> Nature 418: 934 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198537</a>] [<a href="https://doi.org/10.1038/418934a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198537">Rajagopalan et al., 2002</a>; <a href="#75" class="mim-tip-reference" title="Singer, G., Oldt, R., III, Cohen, Y., Wang, B. G., Sidransky, D., Kurman, R. J., Shih, I. E. M. <strong>Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.</strong> J. Nat. Cancer Inst. 95: 484-486, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12644542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12644542</a>] [<a href="https://doi.org/10.1093/jnci/95.6.484" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12644542">Singer et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12644542+12198537+14513361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Flaherty, K. T., Puzanov, I., Kim, K. B., Ribas, A., McArthur, G. A., Sosman, J. A., O'Dwyer, P. J., Lee, R. J., Grippo, J. F., Nolop, K., Chapman, P. B. <strong>Inhibition of mutated, activated BRAF in metastatic melanoma.</strong> New Eng. J. Med. 363: 809-819, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20818844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20818844</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20818844[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1002011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20818844">Flaherty et al. (2010)</a> reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (<a href="/entry/600997">600997</a>), cyclin D1 (<a href="/entry/168461">168461</a>), and Ki67 (MKI67; <a href="/entry/176741">176741</a>) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20818844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bollag, G., Hirth, P., Tsai, J., Zhang, J., Ibrahim, P. N., Cho, H., Spevak, W., Zhang, C., Zhang, Y., Habets, G., Burton, E. A., Wong, B., and 28 others. <strong>Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.</strong> Nature 467: 596-599, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20823850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20823850</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20823850[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20823850">Bollag et al. (2010)</a> described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. <a href="#2" class="mim-tip-reference" title="Bollag, G., Hirth, P., Tsai, J., Zhang, J., Ibrahim, P. N., Cho, H., Spevak, W., Zhang, C., Zhang, Y., Habets, G., Burton, E. A., Wong, B., and 28 others. <strong>Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.</strong> Nature 467: 596-599, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20823850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20823850</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20823850[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20823850">Bollag et al. (2010)</a> concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20823850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. <a href="#29" class="mim-tip-reference" title="Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., Emery, C. M., Stransky, N., Cogdill, A. P., Barretina, J., Caponigro, G., Hieronymus, H., and 23 others. <strong>COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.</strong> Nature 468: 968-972, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21107320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21107320</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21107320[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21107320">Johannessen et al. (2010)</a> identified MAP3K8 (<a href="/entry/191195">191195</a>), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. <a href="#29" class="mim-tip-reference" title="Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., Emery, C. M., Stransky, N., Cogdill, A. P., Barretina, J., Caponigro, G., Hieronymus, H., and 23 others. <strong>COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.</strong> Nature 468: 968-972, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21107320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21107320</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21107320[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21107320">Johannessen et al. (2010)</a> further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21107320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Nazarian, R., Shi, H., Wang, Q., Kong, X., Koya, R. C., Lee, H., Chen, Z., Lee, M.-K., Attar, N., Sazegar, H., Chodon, T., Nelson, S. F., McArthur, G., Sosman, J. A., Ribas, A., Lo, R. S. <strong>Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.</strong> Nature 468: 973-977, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21107323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21107323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21107323[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21107323">Nazarian et al. (2010)</a> showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (<a href="/entry/173410">173410</a>) upregulation or NRAS (<a href="/entry/164790">164790</a>) mutations but not through secondary mutations in BRAF(V600E). <a href="#55" class="mim-tip-reference" title="Nazarian, R., Shi, H., Wang, Q., Kong, X., Koya, R. C., Lee, H., Chen, Z., Lee, M.-K., Attar, N., Sazegar, H., Chodon, T., Nelson, S. F., McArthur, G., Sosman, J. A., Ribas, A., Lo, R. S. <strong>Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.</strong> Nature 468: 973-977, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21107323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21107323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21107323[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21107323">Nazarian et al. (2010)</a> used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, <a href="#55" class="mim-tip-reference" title="Nazarian, R., Shi, H., Wang, Q., Kong, X., Koya, R. C., Lee, H., Chen, Z., Lee, M.-K., Attar, N., Sazegar, H., Chodon, T., Nelson, S. F., McArthur, G., Sosman, J. A., Ribas, A., Lo, R. S. <strong>Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.</strong> Nature 468: 973-977, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21107323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21107323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21107323[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21107323">Nazarian et al. (2010)</a> showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, <a href="#55" class="mim-tip-reference" title="Nazarian, R., Shi, H., Wang, Q., Kong, X., Koya, R. C., Lee, H., Chen, Z., Lee, M.-K., Attar, N., Sazegar, H., Chodon, T., Nelson, S. F., McArthur, G., Sosman, J. A., Ribas, A., Lo, R. S. <strong>Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.</strong> Nature 468: 973-977, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21107323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21107323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21107323[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21107323">Nazarian et al. (2010)</a> concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21107323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#63" class="mim-tip-reference" title="Poulikakos, P. I., Persaud, Y., Janakiraman, M., Kong, X., Ng, C., Moriceau, G., Shi, H., Atefi, M., Titz, B., Gabay, M. T., Salton, M., Dahlman, K. B., and 12 others. <strong>RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E).</strong> Nature 480: 387-390, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22113612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22113612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22113612[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10662" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22113612">Poulikakos et al. (2011)</a> identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, <a href="#63" class="mim-tip-reference" title="Poulikakos, P. I., Persaud, Y., Janakiraman, M., Kong, X., Ng, C., Moriceau, G., Shi, H., Atefi, M., Titz, B., Gabay, M. T., Salton, M., Dahlman, K. B., and 12 others. <strong>RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E).</strong> Nature 480: 387-390, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22113612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22113612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22113612[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10662" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22113612">Poulikakos et al. (2011)</a> identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. <a href="#63" class="mim-tip-reference" title="Poulikakos, P. I., Persaud, Y., Janakiraman, M., Kong, X., Ng, C., Moriceau, G., Shi, H., Atefi, M., Titz, B., Gabay, M. T., Salton, M., Dahlman, K. B., and 12 others. <strong>RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E).</strong> Nature 480: 387-390, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22113612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22113612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22113612[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10662" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22113612">Poulikakos et al. (2011)</a> concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22113612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#81" class="mim-tip-reference" title="Thakur, M. D., Salangsang, F., Landman, A. S., Sellers, W. R., Pryer, N. K., Levesque, M. P., Dummer, R., McMahon, M., Stuart, D. D. <strong>Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.</strong> Nature 494: 251-255, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23302800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23302800</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23302800[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23302800">Thakur et al. (2013)</a> investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. <a href="#81" class="mim-tip-reference" title="Thakur, M. D., Salangsang, F., Landman, A. S., Sellers, W. R., Pryer, N. K., Levesque, M. P., Dummer, R., McMahon, M., Stuart, D. D. <strong>Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.</strong> Nature 494: 251-255, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23302800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23302800</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23302800[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23302800">Thakur et al. (2013)</a> showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. <a href="#81" class="mim-tip-reference" title="Thakur, M. D., Salangsang, F., Landman, A. S., Sellers, W. R., Pryer, N. K., Levesque, M. P., Dummer, R., McMahon, M., Stuart, D. D. <strong>Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.</strong> Nature 494: 251-255, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23302800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23302800</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23302800[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23302800">Thakur et al. (2013)</a> further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. <a href="#81" class="mim-tip-reference" title="Thakur, M. D., Salangsang, F., Landman, A. S., Sellers, W. R., Pryer, N. K., Levesque, M. P., Dummer, R., McMahon, M., Stuart, D. D. <strong>Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.</strong> Nature 494: 251-255, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23302800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23302800</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23302800[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23302800">Thakur et al. (2013)</a> concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23302800" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using metabolic profiling and functional perturbations, <a href="#34" class="mim-tip-reference" title="Kaplon, J., Zheng, L., Meissl, K., Chaneton, B., Selivanov, V. A., Mackay, G., van der Burg, S. H., Verdegaal, E. M. E., Cascante, M., Shlomi, T., Gottlieb, E., Peeper, D. S. <strong>A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence.</strong> Nature 498: 109-112, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23685455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23685455</a>] [<a href="https://doi.org/10.1038/nature12154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23685455">Kaplon et al. (2013)</a> showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; <a href="/entry/300502">300502</a>) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; <a href="/entry/602524">602524</a>) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; <a href="/entry/615499">615499</a>). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23685455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#80" class="mim-tip-reference" title="Sun, C., Wang, L., Huang, S., Heynen, G. J. J. E., Prahallad, A., Robert, C., Haanen, J., Blank, C., Wesseling, J., Willems, S. M., Zecchin, D., Hobor, S., and 13 others. <strong>Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma.</strong> Nature 508: 118-122, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24670642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24670642</a>] [<a href="https://doi.org/10.1038/nature13121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24670642">Sun et al. (2014)</a> showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (<a href="/entry/131550">131550</a>) expression after the development of resistance to inhibitors of BRAF or MEK (<a href="/entry/176872">176872</a>). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, <a href="#80" class="mim-tip-reference" title="Sun, C., Wang, L., Huang, S., Heynen, G. J. J. E., Prahallad, A., Robert, C., Haanen, J., Blank, C., Wesseling, J., Willems, S. M., Zecchin, D., Hobor, S., and 13 others. <strong>Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma.</strong> Nature 508: 118-122, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24670642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24670642</a>] [<a href="https://doi.org/10.1038/nature13121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24670642">Sun et al. (2014)</a> found that suppression of SRY-box 10 (SOX10; <a href="/entry/602229">602229</a>) in melanoma causes activation of TGF-beta (<a href="/entry/190180">190180</a>) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; <a href="/entry/173410">173410</a>), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. <a href="#80" class="mim-tip-reference" title="Sun, C., Wang, L., Huang, S., Heynen, G. J. J. E., Prahallad, A., Robert, C., Haanen, J., Blank, C., Wesseling, J., Willems, S. M., Zecchin, D., Hobor, S., and 13 others. <strong>Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma.</strong> Nature 508: 118-122, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24670642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24670642</a>] [<a href="https://doi.org/10.1038/nature13121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24670642">Sun et al. (2014)</a> found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. <a href="#80" class="mim-tip-reference" title="Sun, C., Wang, L., Huang, S., Heynen, G. J. J. E., Prahallad, A., Robert, C., Haanen, J., Blank, C., Wesseling, J., Willems, S. M., Zecchin, D., Hobor, S., and 13 others. <strong>Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma.</strong> Nature 508: 118-122, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24670642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24670642</a>] [<a href="https://doi.org/10.1038/nature13121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24670642">Sun et al. (2014)</a> concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24670642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Boussemart, L., Malka-Mahieu, H., Girault, I., Allard, D., Hemmingsson, O., Tomasic, G., Thomas, M., Basmadjian, C., Ribeiro, N., Thuaud, F., Mateus, C., Routier, E., Kamsu-Kom, N., Agoussi, S., Eggermont, A. M., Desaubry, L., Robert, C., Vagner, S. <strong>eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.</strong> Nature 513: 105-109, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25079330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25079330</a>] [<a href="https://doi.org/10.1038/nature13572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25079330">Boussemart et al. (2014)</a> demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (<a href="/entry/133440">133440</a>) cap-binding protein, the eIF4G (<a href="/entry/600495">600495</a>) scaffolding protein, and the eIF4A (<a href="/entry/602641">602641</a>) RNA helicase, is associated with resistance to anti-BRAF (<a href="/entry/164757">164757</a>), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see <a href="/entry/176948">176948</a>) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (<a href="/entry/602223">602223</a>); or increased proapoptotic BMF (<a href="/entry/606266">606266</a>)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. <a href="#3" class="mim-tip-reference" title="Boussemart, L., Malka-Mahieu, H., Girault, I., Allard, D., Hemmingsson, O., Tomasic, G., Thomas, M., Basmadjian, C., Ribeiro, N., Thuaud, F., Mateus, C., Routier, E., Kamsu-Kom, N., Agoussi, S., Eggermont, A. M., Desaubry, L., Robert, C., Vagner, S. <strong>eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.</strong> Nature 513: 105-109, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25079330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25079330</a>] [<a href="https://doi.org/10.1038/nature13572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25079330">Boussemart et al. (2014)</a> concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25079330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Colorectal Carcinoma</em></strong></p><p>
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<a href="#67" class="mim-tip-reference" title="Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. <strong>RAF/RAS oncogenes and mismatch-repair status. (Letter)</strong> Nature 418: 934 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198537</a>] [<a href="https://doi.org/10.1038/418934a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198537">Rajagopalan et al. (2002)</a> identified the V600E mutation in 28 of 330 colorectal tumors (see <a href="/entry/114500">114500</a>) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12198537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Domingo, E., Laiho, P., Ollikainen, M., Pinto, M., Wang, L., French, A. J., Westra, J., Frebourg, T., Espin, E., Armengol, M., Hamelin, R., Yamamoto, H., Hofstra, R. M. W., Seruca, R., Lindblom, A., Peltomaki, P., Thibodeau, S. N., Aaltonen, L. A., Schwartz, S., Jr. <strong>BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing.</strong> J. Med. Genet. 41: 664-668, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15342696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15342696</a>] [<a href="https://doi.org/10.1136/jmg.2004.020651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15342696">Domingo et al. (2004)</a> pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (<a href="/entry/120436">120436</a>) or MSH2 (<a href="/entry/609309">609309</a>). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. <a href="#12" class="mim-tip-reference" title="Domingo, E., Laiho, P., Ollikainen, M., Pinto, M., Wang, L., French, A. J., Westra, J., Frebourg, T., Espin, E., Armengol, M., Hamelin, R., Yamamoto, H., Hofstra, R. M. W., Seruca, R., Lindblom, A., Peltomaki, P., Thibodeau, S. N., Aaltonen, L. A., Schwartz, S., Jr. <strong>BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing.</strong> J. Med. Genet. 41: 664-668, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15342696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15342696</a>] [<a href="https://doi.org/10.1136/jmg.2004.020651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15342696">Domingo et al. (2004)</a> studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; <a href="/entry/120435">120435</a>). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. <a href="#12" class="mim-tip-reference" title="Domingo, E., Laiho, P., Ollikainen, M., Pinto, M., Wang, L., French, A. J., Westra, J., Frebourg, T., Espin, E., Armengol, M., Hamelin, R., Yamamoto, H., Hofstra, R. M. W., Seruca, R., Lindblom, A., Peltomaki, P., Thibodeau, S. N., Aaltonen, L. A., Schwartz, S., Jr. <strong>BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing.</strong> J. Med. Genet. 41: 664-668, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15342696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15342696</a>] [<a href="https://doi.org/10.1136/jmg.2004.020651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15342696">Domingo et al. (2004)</a> concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15342696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Lubomierski, N., Plotz, G., Wormek, M., Engels, K., Kriener, S., Trojan, J., Jungling, B., Zeuzem, S., Raedle, J. <strong>BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors.</strong> Cancer 104: 952-961, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16015629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16015629</a>] [<a href="https://doi.org/10.1002/cncr.21266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16015629">Lubomierski et al. (2005)</a> analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. <a href="#46" class="mim-tip-reference" title="Lubomierski, N., Plotz, G., Wormek, M., Engels, K., Kriener, S., Trojan, J., Jungling, B., Zeuzem, S., Raedle, J. <strong>BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors.</strong> Cancer 104: 952-961, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16015629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16015629</a>] [<a href="https://doi.org/10.1002/cncr.21266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16015629">Lubomierski et al. (2005)</a> concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16015629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#82" class="mim-tip-reference" title="Tol, J., Nagtegaal, I. D., Punt, C. J. A. <strong>BRAF mutation in metastatic colorectal cancer. (Letter)</strong> New Eng. J. Med. 361: 98-99, 2009. Note: Erratum: New Eng. J. Med. 365: 869 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19571295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19571295</a>] [<a href="https://doi.org/10.1056/NEJMc0904160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19571295">Tol et al. (2009)</a> detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. <a href="#82" class="mim-tip-reference" title="Tol, J., Nagtegaal, I. D., Punt, C. J. A. <strong>BRAF mutation in metastatic colorectal cancer. (Letter)</strong> New Eng. J. Med. 361: 98-99, 2009. Note: Erratum: New Eng. J. Med. 365: 869 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19571295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19571295</a>] [<a href="https://doi.org/10.1056/NEJMc0904160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19571295">Tol et al. (2009)</a> suggested that the BRAF mutation may be a negative prognostic factor in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19571295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, <a href="#65" class="mim-tip-reference" title="Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., Bernards, R. <strong>Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.</strong> Nature 483: 100-103, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22281684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22281684</a>] [<a href="https://doi.org/10.1038/nature10868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22281684">Prahallad et al. (2012)</a> performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; <a href="/entry/131550">131550</a>) shows strong synergy with BRAF(V600E) inhibition. <a href="#65" class="mim-tip-reference" title="Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., Bernards, R. <strong>Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.</strong> Nature 483: 100-103, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22281684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22281684</a>] [<a href="https://doi.org/10.1038/nature10868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22281684">Prahallad et al. (2012)</a> found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, <a href="#65" class="mim-tip-reference" title="Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., Bernards, R. <strong>Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.</strong> Nature 483: 100-103, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22281684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22281684</a>] [<a href="https://doi.org/10.1038/nature10868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22281684">Prahallad et al. (2012)</a> found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, <a href="#65" class="mim-tip-reference" title="Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., Bernards, R. <strong>Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.</strong> Nature 483: 100-103, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22281684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22281684</a>] [<a href="https://doi.org/10.1038/nature10868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22281684">Prahallad et al. (2012)</a> found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. <a href="#65" class="mim-tip-reference" title="Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., Bernards, R. <strong>Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.</strong> Nature 483: 100-103, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22281684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22281684</a>] [<a href="https://doi.org/10.1038/nature10868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22281684">Prahallad et al. (2012)</a> concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22281684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Gala, M. K., Mizukami, Y., Le, L. P., Moriichi, K., Austin, T., Yamamoto, M., Lauwers, G. Y., Bardeesy, N., Chung, D. C. <strong>Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.</strong> Gastroenterology 146: 520-529, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24512911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24512911</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24512911[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1053/j.gastro.2013.10.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24512911">Gala et al. (2014)</a> identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; <a href="/entry/617108">617108</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24512911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Papillary Thyroid Carcinoma</em></strong></p><p>
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<a href="#37" class="mim-tip-reference" title="Kimura, E. T., Nikiforova, M. N., Zhu, Z., Knauf, J. A., Nikiforov, Y. E., Fagin, J. A. <strong>High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma.</strong> Cancer Res. 63: 1454-1457, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12670889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12670889</a>]" pmid="12670889">Kimura et al. (2003)</a> identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see <a href="/entry/188550">188550</a>); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see <a href="/entry/164761">164761</a>)/PTC mutations and RAS (see <a href="/entry/190020">190020</a>) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. <a href="#37" class="mim-tip-reference" title="Kimura, E. T., Nikiforova, M. N., Zhu, Z., Knauf, J. A., Nikiforov, Y. E., Fagin, J. A. <strong>High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma.</strong> Cancer Res. 63: 1454-1457, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12670889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12670889</a>]" pmid="12670889">Kimura et al. (2003)</a> concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12670889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#92" class="mim-tip-reference" title="Xing, M., Vasko, V., Tallini, G., Larin, A., Wu, G., Udelsman, R., Ringel, M. D., Ladenson, P. W., Sidransky, D. <strong>BRAF T1796A transversion mutation in various thyroid neoplasms.</strong> J. Clin. Endocr. Metab. 89: 1365-1368, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15001635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15001635</a>] [<a href="https://doi.org/10.1210/jc.2003-031488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15001635">Xing et al. (2004)</a> studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, <a href="#92" class="mim-tip-reference" title="Xing, M., Vasko, V., Tallini, G., Larin, A., Wu, G., Udelsman, R., Ringel, M. D., Ladenson, P. W., Sidransky, D. <strong>BRAF T1796A transversion mutation in various thyroid neoplasms.</strong> J. Clin. Endocr. Metab. 89: 1365-1368, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15001635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15001635</a>] [<a href="https://doi.org/10.1210/jc.2003-031488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15001635">Xing et al. (2004)</a> found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15001635" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#58" class="mim-tip-reference" title="Nikiforova, M. N., Kimura, E. T., Gandhi, M., Biddinger, P. W, Knauf, J. A., Basolo, F., Zhu, Z., Giannini, R., Salvatore, G., Fusco, A., Santoro, M., Fagin, J. A., Nikiforov, Y. E. <strong>BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas.</strong> J. Clin. Endocr. Metab. 88: 5399-5404, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14602780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14602780</a>] [<a href="https://doi.org/10.1210/jc.2003-030838" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14602780">Nikiforova et al. (2003)</a> analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14602780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, <a href="#39" class="mim-tip-reference" title="Kumagai, A., Namba, H., Saenko, V. A., Ashizawa, K., Ohtsuru, A., Ito, M., Ishikawa, N., Sugino, K., Ito, K., Jeremiah, S., Thomas, G. A., Bogdanova, T. I., Tronko, M. D., Nagayasu, T., Shibata, Y., Yamashita, S. <strong>Low frequency of BRAF(T1796A) mutations in childhood thyroid carcinomas.</strong> J. Clin. Endocr. Metab. 89: 4280-4284, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15356022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15356022</a>] [<a href="https://doi.org/10.1210/jc.2004-0172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15356022">Kumagai et al. (2004)</a> examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). <a href="#39" class="mim-tip-reference" title="Kumagai, A., Namba, H., Saenko, V. A., Ashizawa, K., Ohtsuru, A., Ito, M., Ishikawa, N., Sugino, K., Ito, K., Jeremiah, S., Thomas, G. A., Bogdanova, T. I., Tronko, M. D., Nagayasu, T., Shibata, Y., Yamashita, S. <strong>Low frequency of BRAF(T1796A) mutations in childhood thyroid carcinomas.</strong> J. Clin. Endocr. Metab. 89: 4280-4284, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15356022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15356022</a>] [<a href="https://doi.org/10.1210/jc.2004-0172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15356022">Kumagai et al. (2004)</a> concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15356022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#66" class="mim-tip-reference" title="Puxeddu, E., Moretti, S., Elisei, R., Romei, C., Pascucci, R., Martinelli, M., Marino, C., Avenia, N., Rossi, E. D., Fadda, G., Cavaliere, A., Ribacchi, R., Falorni, A., Pontecorvi, A., Pacini, F., Pinchera, A., Santeusanio, F. <strong>BRAFV599E mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas.</strong> J. Clin. Endocr. Metab. 89: 2414-2420, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15126572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15126572</a>] [<a href="https://doi.org/10.1210/jc.2003-031425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15126572">Puxeddu et al. (2004)</a> found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15126572" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#91" class="mim-tip-reference" title="Xing, M., Tufano, R. P., Tufaro, A. P., Basaria, S., Ewertz, M., Rosenbaum, E., Byrne, P. J., Wang, J., Sidransky, D., Ladenson, P. W. <strong>Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer.</strong> J. Clin. Endocr. Metab. 89: 2867-2872, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15181070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15181070</a>] [<a href="https://doi.org/10.1210/jc.2003-032050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15181070">Xing et al. (2004)</a> demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15181070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#93" class="mim-tip-reference" title="Xing, M., Westra, W. H., Tufano, R. P., Cohen, Y., Rosenbaum, E., Rhoden, K. J., Carson, K. A., Vasko, V., Larin, A., Tallini, G., Tolaney, S., Holt, E. H., and 10 others. <strong>BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer.</strong> J. Clin. Endocr. Metab. 90: 6373-6379, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16174717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16174717</a>] [<a href="https://doi.org/10.1210/jc.2005-0987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16174717">Xing et al. (2005)</a> studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16174717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a series of 52 classic PTCs, <a href="#62" class="mim-tip-reference" title="Porra, V., Ferraro-Peyret, C., Durand, C., Selmi-Ruby, S., Giroud, H., Berger-Dutrieux, N., Decaussin, M., Peix, J.-L., Bournaud, C., Orgiazzi, J., Borson-Chazot, F., Dante, R., Rousset, B. <strong>Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas.</strong> J. Clin. Endocr. Metab. 90: 3028-3035, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15687339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15687339</a>] [<a href="https://doi.org/10.1210/jc.2004-1394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15687339">Porra et al. (2005)</a> found that low SLC5A8 (<a href="/entry/608044">608044</a>) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. <a href="#62" class="mim-tip-reference" title="Porra, V., Ferraro-Peyret, C., Durand, C., Selmi-Ruby, S., Giroud, H., Berger-Dutrieux, N., Decaussin, M., Peix, J.-L., Bournaud, C., Orgiazzi, J., Borson-Chazot, F., Dante, R., Rousset, B. <strong>Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas.</strong> J. Clin. Endocr. Metab. 90: 3028-3035, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15687339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15687339</a>] [<a href="https://doi.org/10.1210/jc.2004-1394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15687339">Porra et al. (2005)</a> concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15687339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#84" class="mim-tip-reference" title="Vasko, V., Hu, S., Wu, G., Xing, J. C., Larin, A., Savchenko, V., Trink, B., Xing, M. <strong>High prevalence and possible de novo formation of BRAF mutation in metastasized papillary thyroid cancer in lymph nodes.</strong> J. Clin. Endocr. Metab. 90: 5265-5269, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15998781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15998781</a>] [<a href="https://doi.org/10.1210/jc.2004-2353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15998781">Vasko et al. (2005)</a> studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15998781" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, <a href="/entry/188540">188540</a>; and TDH3, <a href="/entry/274700">274700</a>), who was also found to have multifocal follicular carcinoma of the thyroid, <a href="#24" class="mim-tip-reference" title="Hishinuma, A., Fukata, S., Kakudo, K., Murata, Y., Ieiri, T. <strong>High incidence of thyroid cancer in long-standing goiters with thyroglobulin mutations.</strong> Thyroid 15: 1079-1084, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16187918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16187918</a>] [<a href="https://doi.org/10.1089/thy.2005.15.1079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16187918">Hishinuma et al. (2005)</a> identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16187918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Liu, D., Liu, Z., Condouris, S., Xing, M. <strong>BRAF V600E maintains proliferation, transformation, and tumorigenicity of BRAF-mutant papillary thyroid cancer cells.</strong> J. Clin. Endocr. Metab. 92: 2264-2271, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17374713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17374713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17374713[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2006-1613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17374713">Liu et al. (2007)</a> used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17374713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Jo, Y. S., Li, S., Song, J. H., Kwon, K. H., Lee, J. C., Rha, S. Y., Lee, H. J., Sul, J. Y., Kweon, G. R., Ro, H., Kim, J.-M., Shong, M. <strong>Influence of the BRAF V600E mutation on expression of vascular endothelial growth factor in papillary thyroid cancer.</strong> J. Clin. Endocr. Metab. 91: 3667-3670, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16772349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16772349</a>] [<a href="https://doi.org/10.1210/jc.2005-2836" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16772349">Jo et al. (2006)</a> found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; <a href="/entry/192240">192240</a>) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. <a href="#28" class="mim-tip-reference" title="Jo, Y. S., Li, S., Song, J. H., Kwon, K. H., Lee, J. C., Rha, S. Y., Lee, H. J., Sul, J. Y., Kweon, G. R., Ro, H., Kim, J.-M., Shong, M. <strong>Influence of the BRAF V600E mutation on expression of vascular endothelial growth factor in papillary thyroid cancer.</strong> J. Clin. Endocr. Metab. 91: 3667-3670, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16772349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16772349</a>] [<a href="https://doi.org/10.1210/jc.2005-2836" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16772349">Jo et al. (2006)</a> concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16772349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Durante, C., Puxeddu, E., Ferretti, E., Morisi, R., Moretti, S., Bruno, R., Barbi, F., Avenia, N., Scipioni, A., Verrienti, A., Tosi, E., Cavaliere, A., Gulino, A., Filetti, S., Russo, D. <strong>BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism.</strong> J. Clin. Endocr. Metab. 92: 2840-2843, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17488796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17488796</a>] [<a href="https://doi.org/10.1210/jc.2006-2707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17488796">Durante et al. (2007)</a> found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17488796" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Lupi, C., Giannini, R., Ugolini, C., Proietti, A., Berti, P., Minuto, M., Materazzi, G., Elisei, R., Santoro, M., Miccoli, P., Basolo, F. <strong>Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma.</strong> J. Clin. Endocr. Metab. 92: 4085-4090, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17785355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17785355</a>] [<a href="https://doi.org/10.1210/jc.2007-1179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17785355">Lupi et al. (2007)</a> found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17785355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Flaherty, K. T., Puzanov, I., Kim, K. B., Ribas, A., McArthur, G. A., Sosman, J. A., O'Dwyer, P. J., Lee, R. J., Grippo, J. F., Nolop, K., Chapman, P. B. <strong>Inhibition of mutated, activated BRAF in metastatic melanoma.</strong> New Eng. J. Med. 363: 809-819, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20818844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20818844</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20818844[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1002011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20818844">Flaherty et al. (2010)</a> reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20818844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Nonseminomatous Germ Cell Tumors</em></strong></p><p>
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In 3 (9%) of 32 nonseminomatous germ cell tumors (see <a href="/entry/273300">273300</a>) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, <a href="#79" class="mim-tip-reference" title="Sommerer, F., Hengge, U. R., Markwarth, A., Vomschloss, S., Stolzenburg, J.-U., Wittekind, C., Tannapfel, A. <strong>Mutations of BRAF and RAS are rare events in germ cell tumours.</strong> Int. J. Cancer 113: 329-335, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15386408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15386408</a>] [<a href="https://doi.org/10.1002/ijc.20567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15386408">Sommerer et al. (2005)</a> identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15386408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Astrocytoma</em></strong></p><p>
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<a href="#60" class="mim-tip-reference" title="Pfister, S., Janzarik, W. G., Remke, M., Ernst, A., Werft, W., Becker, N., Toedt, G., Wittmann, A., Kratz, C., Olbrich, H., Ahmadi, R., Thieme, B., and 11 others. <strong>BRAF gene duplication constitutes a mechanism of MAPK activation in low-grade astrocytomas.</strong> J. Clin. Invest. 118: 1739-1749, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18398503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18398503</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18398503[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI33656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18398503">Pfister et al. (2008)</a> identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see <a href="/entry/137800">137800</a>). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (<a href="/entry/176948">176948</a>) pathway activation in these tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18398503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Neurodegeneration</em></strong></p><p>
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<a href="#49" class="mim-tip-reference" title="Mass, E., Jacome-Galarza, C. E., Blank, T., Lazarov, T., Durham, B. H., Ozkaya, N., Pastore, A., Schwabenland, M., Chung, Y. R., Rosenblum, M. K., Prinz, M., Abdel-Wahab, O., Geissmann, F. <strong>A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease.</strong> Nature 549: 389-393, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28854169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28854169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28854169[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature23672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28854169">Mass et al. (2017)</a> hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. <a href="#49" class="mim-tip-reference" title="Mass, E., Jacome-Galarza, C. E., Blank, T., Lazarov, T., Durham, B. H., Ozkaya, N., Pastore, A., Schwabenland, M., Chung, Y. R., Rosenblum, M. K., Prinz, M., Abdel-Wahab, O., Geissmann, F. <strong>A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease.</strong> Nature 549: 389-393, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28854169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28854169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28854169[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature23672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28854169">Mass et al. (2017)</a> showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. <a href="#49" class="mim-tip-reference" title="Mass, E., Jacome-Galarza, C. E., Blank, T., Lazarov, T., Durham, B. H., Ozkaya, N., Pastore, A., Schwabenland, M., Chung, Y. R., Rosenblum, M. K., Prinz, M., Abdel-Wahab, O., Geissmann, F. <strong>A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease.</strong> Nature 549: 389-393, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28854169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28854169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28854169[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature23672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28854169">Mass et al. (2017)</a> suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28854169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Function</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Brady, D. C., Crowe, M. S., Turski, M. L., Hobbs, G. A., Yao, X., Chaikuad, A., Knapp, S., Xiao, K., Campbell, S. L., Thiele, D. J., Counter, C. M. <strong>Copper is required for oncogenic BRAF signalling and tumorigenesis.</strong> Nature 509: 492-496, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24717435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24717435</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24717435[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24717435">Brady et al. (2014)</a> showed that decreasing the levels of CTR1 (<a href="/entry/603085">603085</a>), or mutations in MEK1 (<a href="/entry/176872">176872</a>) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (<a href="/entry/602520">602520</a>) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (<a href="/entry/277900">277900</a>) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. <a href="#4" class="mim-tip-reference" title="Brady, D. C., Crowe, M. S., Turski, M. L., Hobbs, G. A., Yao, X., Chaikuad, A., Knapp, S., Xiao, K., Campbell, S. L., Thiele, D. J., Counter, C. M. <strong>Copper is required for oncogenic BRAF signalling and tumorigenesis.</strong> Nature 509: 492-496, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24717435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24717435</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24717435[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24717435">Brady et al. (2014)</a> concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24717435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#69" class="mim-tip-reference" title="Rapino, F., Delaunay, S., Rambow, F., Zhou, Z., Tharun, L., De Tullio, P., Sin, O., Shostak, K., Schmitz, S., Piepers, J., Ghesquiere, B., Karim, L., and 17 others. <strong>Codon-specific translation reprogramming promotes resistance to targeted therapy.</strong> Nature 558: 605-609, 2018. Note: Erratum: Nature 599: E14, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29925953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29925953</a>] [<a href="https://doi.org/10.1038/s41586-018-0243-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29925953">Rapino et al. (2018)</a> showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. <a href="#69" class="mim-tip-reference" title="Rapino, F., Delaunay, S., Rambow, F., Zhou, Z., Tharun, L., De Tullio, P., Sin, O., Shostak, K., Schmitz, S., Piepers, J., Ghesquiere, B., Karim, L., and 17 others. <strong>Codon-specific translation reprogramming promotes resistance to targeted therapy.</strong> Nature 558: 605-609, 2018. Note: Erratum: Nature 599: E14, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29925953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29925953</a>] [<a href="https://doi.org/10.1038/s41586-018-0243-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29925953">Rapino et al. (2018)</a> showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (<a href="/entry/612722">612722</a>) or CTU1 (<a href="/entry/612694">612694</a>) and/or CTU2 (<a href="/entry/617057">617057</a>) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (<a href="/entry/603348">603348</a>) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. <a href="#69" class="mim-tip-reference" title="Rapino, F., Delaunay, S., Rambow, F., Zhou, Z., Tharun, L., De Tullio, P., Sin, O., Shostak, K., Schmitz, S., Piepers, J., Ghesquiere, B., Karim, L., and 17 others. <strong>Codon-specific translation reprogramming promotes resistance to targeted therapy.</strong> Nature 558: 605-609, 2018. Note: Erratum: Nature 599: E14, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29925953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29925953</a>] [<a href="https://doi.org/10.1038/s41586-018-0243-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29925953">Rapino et al. (2018)</a> concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29925953" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177032 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177032;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014995" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014995" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014995</a>
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<p>In 1 case of colorectal cancer (see <a href="/entry/114500">114500</a>), <a href="#67" class="mim-tip-reference" title="Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. <strong>RAF/RAS oncogenes and mismatch-repair status. (Letter)</strong> Nature 418: 934 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198537</a>] [<a href="https://doi.org/10.1038/418934a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198537">Rajagopalan et al. (2002)</a> observed a G-to-T transversion at nucleotide 1382 of the BRAF gene, resulting in an arg-ile substitution at codon 461 (R461I), in heterozygous state and as a somatic mutation. Based on the revised numbering system of <a href="#40" class="mim-tip-reference" title="Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., Hemminki, K. <strong>BRAF mutations in metastatic melanoma: a possible association with clinical outcome.</strong> Clin. Cancer Res. 9: 3362-3368, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960123</a>]" pmid="12960123">Kumar et al. (2003)</a>, the ARG461ILE (1382G-T) mutation has been renumbered as ARG462ILE (1385G-T). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12198537+12960123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 COLORECTAL CANCER, SOMATIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177033 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177033;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014996" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014996" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014996</a>
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<p>In a colorectal tumor (see <a href="/entry/114500">114500</a>), <a href="#67" class="mim-tip-reference" title="Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. <strong>RAF/RAS oncogenes and mismatch-repair status. (Letter)</strong> Nature 418: 934 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198537</a>] [<a href="https://doi.org/10.1038/418934a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198537">Rajagopalan et al. (2002)</a> identified a T-to-G transversion at nucleotide 1385 of the BRAF gene, resulting in an ile-ser substitution at codon 462 (I462S). This mutation was found in heterozygosity and was shown to be somatic. Based on the revised numbering system of <a href="#40" class="mim-tip-reference" title="Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., Hemminki, K. <strong>BRAF mutations in metastatic melanoma: a possible association with clinical outcome.</strong> Clin. Cancer Res. 9: 3362-3368, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960123</a>]" pmid="12960123">Kumar et al. (2003)</a>, the ILE462SER (1385T-G) mutation has been renumbered as ILE463SER (1388T-G). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12198537+12960123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0004" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0004 COLORECTAL CANCER, SOMATIC</strong>
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BRAF, GLY464GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913348 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913348;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014997 OR RCV000033304 OR RCV000207512 OR RCV000844618 OR RCV001261044" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014997, RCV000033304, RCV000207512, RCV000844618, RCV001261044" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014997...</a>
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<p>In a colorectal tumor (see <a href="/entry/114500">114500</a>), <a href="#67" class="mim-tip-reference" title="Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. <strong>RAF/RAS oncogenes and mismatch-repair status. (Letter)</strong> Nature 418: 934 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198537</a>] [<a href="https://doi.org/10.1038/418934a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198537">Rajagopalan et al. (2002)</a> identified a G-to-A transition at nucleotide 1388 of the BRAF gene, resulting in a gly-glu substitution at codon 463 (G463E). This mutation was heterozygous and somatic. Based on the revised numbering system of <a href="#40" class="mim-tip-reference" title="Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., Hemminki, K. <strong>BRAF mutations in metastatic melanoma: a possible association with clinical outcome.</strong> Clin. Cancer Res. 9: 3362-3368, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960123</a>]" pmid="12960123">Kumar et al. (2003)</a>, the GLY463GLU (1388G-A) mutation has been renumbered as GLY464GLU (1391G-A). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12198537+12960123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 COLORECTAL CANCER, SOMATIC</strong>
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THYROID CARCINOMA, FOLLICULAR, SOMATIC, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913364 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913364;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121913364?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014999 OR RCV000015000 OR RCV000037938 OR RCV000433498" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014999, RCV000015000, RCV000037938, RCV000433498" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014999...</a>
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<p><strong><em>Colorectal Cancer</em></strong></p><p>
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In a colorectal tumor (see <a href="/entry/114500">114500</a>), <a href="#67" class="mim-tip-reference" title="Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. <strong>RAF/RAS oncogenes and mismatch-repair status. (Letter)</strong> Nature 418: 934 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198537</a>] [<a href="https://doi.org/10.1038/418934a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198537">Rajagopalan et al. (2002)</a> identified an A-to-G transition at nucleotide 1798 of the BRAF gene, resulting in a lys-glu at codon 600 (K600E). This mutation was heterozygous and occurred somatically. Based on the revised numbering system of <a href="#40" class="mim-tip-reference" title="Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., Hemminki, K. <strong>BRAF mutations in metastatic melanoma: a possible association with clinical outcome.</strong> Clin. Cancer Res. 9: 3362-3368, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960123</a>]" pmid="12960123">Kumar et al. (2003)</a>, the LYS600GLU (1798A-G) mutation has been renumbered as LYS601GLU (1801A-G). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12198537+12960123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Thyroid Carcinoma, Follicular</em></strong></p><p>
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In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, <a href="/entry/188540">188540</a>; and TDH3, <a href="/entry/274700">274700</a>), who was also found to have multifocal follicular carcinoma of the thyroid, <a href="#24" class="mim-tip-reference" title="Hishinuma, A., Fukata, S., Kakudo, K., Murata, Y., Ieiri, T. <strong>High incidence of thyroid cancer in long-standing goiters with thyroglobulin mutations.</strong> Thyroid 15: 1079-1084, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16187918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16187918</a>] [<a href="https://doi.org/10.1089/thy.2005.15.1079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16187918">Hishinuma et al. (2005)</a> identified somatic heterozygosity for the K601E mutation in the BRAF gene in the cancerous thyroid tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16187918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<strong>.0006 ADENOCARCINOMA OF LUNG, SOMATIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913351 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913351;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121913351?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015001 OR RCV000037916" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015001, RCV000037916" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015001...</a>
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<p><a href="#54" class="mim-tip-reference" title="Naoki, K., Chen, T.-H., Richards, W. G., Sugarbaker, D. J., Meyerson, M. <strong>Missense mutations of the BRAF gene in human lung adenocarcinoma.</strong> Cancer Res. 62: 7001-7003, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12460919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12460919</a>]" pmid="12460919">Naoki et al. (2002)</a> identified a gly465-to-val (G465V) mutation in exon 11 of the BRAF gene in 1 of 127 primary human lung adenocarcinomas (see <a href="/entry/211980">211980</a>) screened. Based on the revised numbering system of <a href="#40" class="mim-tip-reference" title="Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., Hemminki, K. <strong>BRAF mutations in metastatic melanoma: a possible association with clinical outcome.</strong> Clin. Cancer Res. 9: 3362-3368, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960123</a>]" pmid="12960123">Kumar et al. (2003)</a>, the GLY465VAL mutation has been renumbered as GLY466VAL. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12460919+12960123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913366 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913366;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015002" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015002" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015002</a>
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<p><a href="#54" class="mim-tip-reference" title="Naoki, K., Chen, T.-H., Richards, W. G., Sugarbaker, D. J., Meyerson, M. <strong>Missense mutations of the BRAF gene in human lung adenocarcinoma.</strong> Cancer Res. 62: 7001-7003, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12460919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12460919</a>]" pmid="12460919">Naoki et al. (2002)</a> identified a leu596-to-arg (L596R) mutation in exon 15 of the BRAF gene in 1 of 127 primary human lung adenocarcinomas (see <a href="/entry/211980">211980</a>) screened. Based on the revised numbering system of <a href="#40" class="mim-tip-reference" title="Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., Hemminki, K. <strong>BRAF mutations in metastatic melanoma: a possible association with clinical outcome.</strong> Clin. Cancer Res. 9: 3362-3368, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960123</a>]" pmid="12960123">Kumar et al. (2003)</a>, the LEU596ARG mutation has been renumbered as LEU597ARG. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12460919+12960123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 NONSMALL CELL LUNG CANCER, SOMATIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913369 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913369;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121913369?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015003 OR RCV000030948 OR RCV000033333 OR RCV000208539 OR RCV000505705 OR RCV001813207 OR RCV002271369 OR RCV002513056" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015003, RCV000030948, RCV000033333, RCV000208539, RCV000505705, RCV001813207, RCV002271369, RCV002513056" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015003...</a>
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<p>In a nonsmall cell lung carcinoma (see <a href="/entry/211980">211980</a>), <a href="#5" class="mim-tip-reference" title="Brose, M. S., Volpe, P., Feldman, M., Kumar, M., Rishi, I., Gerrero, R., Einhorn, E., Herlyn, M., Minna, J., Nicholson, A., Roth, J. A., Albelda, S. M., Davies, H., Cox, C., Brignell, G., Stephens, P., Futreal, P. A., Wooster, R., Stratton, M. R., Weber, B. L. <strong>BRAF and RAS mutations in human lung cancer and melanoma.</strong> Cancer Res. 62: 6997-7000, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12460918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12460918</a>]" pmid="12460918">Brose et al. (2002)</a> identified a leu596-to-val (L596V) change in exon 15 of the BRAF gene. Based on the revised numbering system of <a href="#40" class="mim-tip-reference" title="Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., Hemminki, K. <strong>BRAF mutations in metastatic melanoma: a possible association with clinical outcome.</strong> Clin. Cancer Res. 9: 3362-3368, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960123</a>]" pmid="12960123">Kumar et al. (2003)</a>, the LEU596VAL mutation has been renumbered as LEU597VAL. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12460918+12960123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 LYMPHOMA, NON-HODGKIN, SOMATIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913357 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913357;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015004 OR RCV000033306 OR RCV001778653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015004, RCV000033306, RCV001778653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015004...</a>
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<p><a href="#44" class="mim-tip-reference" title="Lee, J. W., Yoo, N. J., Soung, Y. H., Kim, H. S., Park, W. S., Kim, S. Y., Lee, J. H., Park, J. Y., Cho, Y. G., Kim, C. J., Ko, Y. H., Kim, S. H., Nam, S. W., Lee, J. Y., Lee, S. H. <strong>BRAF mutations in non-Hodgkin's lymphoma.</strong> Brit. J. Cancer 89: 1958-1960, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14612909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14612909</a>] [<a href="https://doi.org/10.1038/sj.bjc.6601371" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14612909">Lee et al. (2003)</a> analyzed genomic DNA from 164 non-Hodgkin lymphomas (NHLs; see <a href="/entry/605027">605027</a>) by PCR-based single-strand conformation polymorphism (SSCP) for detection of somatic mutations of BRAF (exons 11 and 15). BRAF mutations were detected in 4 NHLs (2.4%). Whereas most BRAF mutations in human cancers involve val600, e.g., <a href="#0001">164757.0001</a>, all of the 4 BRAF mutations in the NHLs involved other amino acids: 1 G468A (<a href="#0010">164757.0010</a>), 2 G468R, and 1 D593G (<a href="#0011">164757.0011</a>). Based on the revised numbering system of <a href="#40" class="mim-tip-reference" title="Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., Hemminki, K. <strong>BRAF mutations in metastatic melanoma: a possible association with clinical outcome.</strong> Clin. Cancer Res. 9: 3362-3368, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960123</a>]" pmid="12960123">Kumar et al. (2003)</a>, the GLY468ARG mutation has been renumbered as GLY469ARG, the GLY468ALA mutation has been renumbered as GLY469ALA, and the ASP593GLY mutation has been renumbered as ASP594GLY. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14612909+12960123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 LYMPHOMA, NON-HODGKIN, SOMATIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913355 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913355;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121913355?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015005 OR RCV000150210" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015005, RCV000150210" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015005...</a>
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<p>For discussion of the gly469-to-ala (G469A) mutation in the BRAF gene that was found in compound heterozygous state in genomic DNA from 164 non-Hodgkin lymphomas (see <a href="/entry/605027">605027</a>) by <a href="#44" class="mim-tip-reference" title="Lee, J. W., Yoo, N. J., Soung, Y. H., Kim, H. S., Park, W. S., Kim, S. Y., Lee, J. H., Park, J. Y., Cho, Y. G., Kim, C. J., Ko, Y. H., Kim, S. H., Nam, S. W., Lee, J. Y., Lee, S. H. <strong>BRAF mutations in non-Hodgkin's lymphoma.</strong> Brit. J. Cancer 89: 1958-1960, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14612909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14612909</a>] [<a href="https://doi.org/10.1038/sj.bjc.6601371" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14612909">Lee et al. (2003)</a>, see <a href="#0009">164757.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14612909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 LYMPHOMA, NON-HODGKIN, SOMATIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913338 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913338;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015006 OR RCV000037932 OR RCV000426107 OR RCV001238853" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015006, RCV000037932, RCV000426107, RCV001238853" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015006...</a>
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<p>For discussion of the asp594-to-gly (D594G) mutation in the BRAF gene that was found in compound heterozygous state in genomic DNA from 164 non-Hodgkin lymphomas (see <a href="/entry/605027">605027</a>) by <a href="#44" class="mim-tip-reference" title="Lee, J. W., Yoo, N. J., Soung, Y. H., Kim, H. S., Park, W. S., Kim, S. Y., Lee, J. H., Park, J. Y., Cho, Y. G., Kim, C. J., Ko, Y. H., Kim, S. H., Nam, S. W., Lee, J. Y., Lee, S. H. <strong>BRAF mutations in non-Hodgkin's lymphoma.</strong> Brit. J. Cancer 89: 1958-1960, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14612909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14612909</a>] [<a href="https://doi.org/10.1038/sj.bjc.6601371" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14612909">Lee et al. (2003)</a>, see <a href="#0009">164757.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14612909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177034 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177034;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014998 OR RCV000033285 OR RCV000208416 OR RCV000235118 OR RCV000678900 OR RCV001047900 OR RCV003150930 OR RCV003338381" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014998, RCV000033285, RCV000208416, RCV000235118, RCV000678900, RCV001047900, RCV003150930, RCV003338381" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014998...</a>
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<p>In 2 unrelated patients with cardiofaciocutaneous syndrome (CFC1; <a href="/entry/115150">115150</a>), <a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> found a heterozygous 736G-C transversion in exon 6 of the BRAF gene, predicting an ala246-to-pro (A246P) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
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BRAF, GLN257ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177035 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177035;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015007 OR RCV000033289 OR RCV000080904 OR RCV000208766 OR RCV001027771 OR RCV001261967 OR RCV001329219 OR RCV001813208 OR RCV001813744 OR RCV003224098 OR RCV004018628 OR RCV004752707" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015007, RCV000033289, RCV000080904, RCV000208766, RCV001027771, RCV001261967, RCV001329219, RCV001813208, RCV001813744, RCV003224098, RCV004018628, RCV004752707" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015007...</a>
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<p>In 3 unrelated patients with cardiofaciocutaneous syndrome (CFC1; <a href="/entry/115150">115150</a>), <a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> found a heterozygous 770A-G transition in exon 6 of the BRAF gene, predicting a gln257-to-arg (Q257R) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0014 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
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</h4>
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BRAF, GLY469GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913355 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913355;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121913355?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015008 OR RCV000033307 OR RCV000211748 OR RCV000212152 OR RCV000506575 OR RCV001813209 OR RCV002287336 OR RCV003450641" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015008, RCV000033307, RCV000211748, RCV000212152, RCV000506575, RCV001813209, RCV002287336, RCV003450641" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015008...</a>
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<p>In 4 presumably unrelated individuals with cardiofaciocutaneous syndrome (CFC1; <a href="/entry/115150">115150</a>), <a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> found a heterozygous 1406G-A transition in exon 11 of the BRAF gene, predicting a gly469-to-glu (G469E) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0015" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0015 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
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</span>
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</h4>
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BRAF, LEU485PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177036 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177036;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177036" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177036" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015009 OR RCV000208764 OR RCV000211749 OR RCV000680805 OR RCV001172276 OR RCV001849264 OR RCV003415705 OR RCV004018629" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015009, RCV000208764, RCV000211749, RCV000680805, RCV001172276, RCV001849264, RCV003415705, RCV004018629" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015009...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cardiofaciocutaneous syndrome (CFC1; <a href="/entry/115150">115150</a>), <a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> found a heterozygous 1455G-C transversion in exon 12 of the BRAF gene, predicting a leu485-to-phe (L485F) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0016" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0016 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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BRAF, LYS499GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177037;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015010 OR RCV000207517 OR RCV000779848 OR RCV001813210 OR RCV004795412" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015010, RCV000207517, RCV000779848, RCV001813210, RCV004795412" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015010...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cardiofaciocutaneous syndrome (CFC1; <a href="/entry/115150">115150</a>), <a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> found a heterozygous 1495A-G transition in exon 12 of the BRAF gene, predicting a lys499-to-glu (K499E) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177038 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177038;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015011 OR RCV000033315 OR RCV000207513 OR RCV000844616 OR RCV004018630" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015011, RCV000033315, RCV000207513, RCV000844616, RCV004018630" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015011...</a>
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<p>In a patient with cardiofaciocutaneous syndrome (CFC1; <a href="/entry/115150">115150</a>), who was previously reported by <a href="#85" class="mim-tip-reference" title="Verloes, A., Le Merrer, M., Soyeur, D., Kaplan, J., Pangalos, C., Rigo, J., Briard, M.-L. <strong>CFC syndrome: a syndrome distinct from Noonan syndrome.</strong> Ann. Genet. 31: 230-234, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3265306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3265306</a>]" pmid="3265306">Verloes et al. (1988)</a>, <a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> found a heterozygous 1501G-A transition in exon 12 of the BRAF gene, predicting a glu501-to-lys (E501K) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16474404+3265306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177039 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177039;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015012 OR RCV000207518 OR RCV000211750 OR RCV000414915 OR RCV000808147 OR RCV001273349" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015012, RCV000207518, RCV000211750, RCV000414915, RCV000808147, RCV001273349" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015012...</a>
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<p>In 2 presumably unrelated patients with cardiofaciocutaneous syndrome (CFC1; <a href="/entry/115150">115150</a>), <a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> found a heterozygous 1502A-G transition in exon 12 of the BRAF gene, predicting a glu501-to-gly (E501G) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177040 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177040;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015013 OR RCV000033329 OR RCV000211751 OR RCV000474979 OR RCV003450642 OR RCV004018631" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015013, RCV000033329, RCV000211751, RCV000474979, RCV003450642, RCV004018631" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015013...</a>
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<p>In 2 presumably unrelated patients with cardiofaciocutaneous syndrome (CFC1; <a href="/entry/115150">115150</a>), <a href="#57" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. <strong>Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.</strong> Nature Genet. 38: 294-296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474404</a>] [<a href="https://doi.org/10.1038/ng1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474404">Niihori et al. (2006)</a> found a heterozygous 1741A-G transition in exon 14 of the BRAF gene, predicting an asn581-to-asp (N581D) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0020 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177041 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177041;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015014 OR RCV000208775 OR RCV000623633 OR RCV000779634 OR RCV001257953" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015014, RCV000208775, RCV000623633, RCV000779634, RCV001257953" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015014...</a>
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<p>In a 7-year-old boy with craniofacial features overlapping both cardiofaciocutaneous (CFC1; <a href="/entry/115150">115150</a>) and Costello (<a href="/entry/218040">218040</a>) syndromes, in whom no HRAS (<a href="/entry/190020">190020</a>) mutation was found (<a href="#16" class="mim-tip-reference" title="Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., Rauen, K. A. <strong>HRAS mutation in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.</strong> Am. J. Med. Genet. 140A: 8-16, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16372351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16372351</a>] [<a href="https://doi.org/10.1002/ajmg.a.31078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16372351">Estep et al., 2006</a>), <a href="#70" class="mim-tip-reference" title="Rauen, K. A. <strong>Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. (Letter)</strong> Am. J. Med. Genet. 140A: 1681-1683, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804887</a>] [<a href="https://doi.org/10.1002/ajmg.a.31315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804887">Rauen (2006)</a> identified a 1600G-C transversion in exon 13 of the BRAF gene, resulting in a gly534-to-arg (G534R) substitution, and noted that CFC-causing BRAF mutations had not previously been described in exon 13. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16804887+16372351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0021" class="mim-anchor"></a>
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<strong>.0021 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs180177042 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs180177042;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs180177042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs180177042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015015 OR RCV000033337 OR RCV000622900 OR RCV000763164 OR RCV001851863" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015015, RCV000033337, RCV000622900, RCV000763164, RCV001851863" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015015...</a>
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<p>In a 13-year-old girl with phenotypic features overlapping cardiofaciocutaneous (CFC1; <a href="/entry/115150">115150</a>) and Costello (<a href="/entry/218040">218040</a>) syndromes, in whom no HRAS (<a href="/entry/190020">190020</a>) mutation was found (<a href="#16" class="mim-tip-reference" title="Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., Rauen, K. A. <strong>HRAS mutation in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.</strong> Am. J. Med. Genet. 140A: 8-16, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16372351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16372351</a>] [<a href="https://doi.org/10.1002/ajmg.a.31078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16372351">Estep et al., 2006</a>), <a href="#70" class="mim-tip-reference" title="Rauen, K. A. <strong>Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. (Letter)</strong> Am. J. Med. Genet. 140A: 1681-1683, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804887</a>] [<a href="https://doi.org/10.1002/ajmg.a.31315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804887">Rauen (2006)</a> identified a 1914T-A transversion in exon 16 of the BRAF gene, resulting in an asp638-to-glu (D638E) substitution, and noted that CFC-causing BRAF mutations had not previously been described in exon 16. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16804887+16372351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906660 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906660;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906660?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022678 OR RCV000033281 OR RCV000208540 OR RCV000211753 OR RCV000515432 OR RCV000545320 OR RCV001329218 OR RCV003230371 OR RCV003398558" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022678, RCV000033281, RCV000208540, RCV000211753, RCV000515432, RCV000545320, RCV001329218, RCV003230371, RCV003398558" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022678...</a>
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<p>In a patient with Noonan syndrome-7 (NS7; <a href="/entry/613706">613706</a>), <a href="#73" class="mim-tip-reference" title="Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others. <strong>Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.</strong> Hum. Mutat. 30: 695-702, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19206169[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206169">Sarkozy et al. (2009)</a> identified a heterozygous de novo 722C-T transition in exon 6 of the BRAF gene, resulting in a thr241-to-met (T241M) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906660 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906660;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906660?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022679 OR RCV000208548 OR RCV000624512 OR RCV001703420 OR RCV002513171" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022679, RCV000208548, RCV000624512, RCV001703420, RCV002513171" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022679...</a>
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<p>In a patient with Noonan syndrome-7 (NS7; <a href="/entry/613706">613706</a>), <a href="#73" class="mim-tip-reference" title="Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others. <strong>Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.</strong> Hum. Mutat. 30: 695-702, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19206169[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206169">Sarkozy et al. (2009)</a> identified a heterozygous 722C-G transversion in exon 6 of the BRAF gene, resulting in a thr241-to-arg (T241R) substitution. The mutation was not identified in 150 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0024 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906661 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906661;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022680 OR RCV000022681 OR RCV000055896 OR RCV000207516 OR RCV000211752 OR RCV000515363 OR RCV000654966 OR RCV001089761 OR RCV002288517" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022680, RCV000022681, RCV000055896, RCV000207516, RCV000211752, RCV000515363, RCV000654966, RCV001089761, RCV002288517" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022680...</a>
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<p><strong><em>Cardiofaciocutaneous Syndrome 1</em></strong></p><p>
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In 2 unrelated patients with cardiofaciocutaneous syndrome (CFC1; <a href="/entry/115150">115150</a>), <a href="#74" class="mim-tip-reference" title="Schulz, A. L., Albrecht, B., Arici, C., van der Burgt, I., Buske, A., Gillessen-Kaesbach, G., Heller, R., Horn, D., Hubner, C. A., Korenke, G. C., Konig, R., Kress, W., and 15 others. <strong>Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome</strong> Clin. Genet. 73: 62-70, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18042262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18042262</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00931.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18042262">Schulz et al. (2008)</a> identified a heterozygous 721A-C transversion in exon 6 of the BRAF gene, resulting in a thr241-to-pro (T241P) substitution in a conserved residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18042262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>LEOPARD Syndrome 3</em></strong></p><p>
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<a href="#73" class="mim-tip-reference" title="Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others. <strong>Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.</strong> Hum. Mutat. 30: 695-702, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19206169[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206169">Sarkozy et al. (2009)</a> identified a heterozygous de novo T241P mutation in a patient with LEOPARD syndrome-3 (LPRD3; <a href="/entry/613707">613707</a>). The patient had poor growth, craniofacial anomalies, short and webbed neck, mitral and aortic valve dysplasia, cognitive deficits, neonatal hypotonia, sensorineural deafness, and seizures. Other features included thorax defects, delayed puberty, reduced bone density, and fibrous cystic lesions of the pelvis. The skin showed hyperkeratosis, cafe-au-lait spots, multiple nevi, and dark colored lentigines that were spread on the whole body including the palms and soles. In vitro functional expression studies showed that the T241P mutant protein did not show transforming ability to cells in vitro, although there was a slight increase in MEK phosphorylation, suggesting activation of the downstream MAPK pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231228 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231228;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs606231228" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs606231228" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022682 OR RCV000191066 OR RCV000208560 OR RCV001781297" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022682, RCV000191066, RCV000208560, RCV001781297" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022682...</a>
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<p>In 2 unrelated patients with Noonan syndrome-7 (NS7; <a href="/entry/613706">613706</a>), <a href="#73" class="mim-tip-reference" title="Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others. <strong>Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.</strong> Hum. Mutat. 30: 695-702, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19206169[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206169">Sarkozy et al. (2009)</a> identified a heterozygous de novo 1593G-C transversion in exon 13 of the BRAF gene, resulting in a trp531-to-cys (W531C) substitution. In vitro functional expression studies showed that the W531C mutant protein did not show transforming ability to cells in vitro, although there was a slight increase in MEK phosphorylation, suggesting activation of the downstream MAPK pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0026 NOONAN SYNDROME 7</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015003 OR RCV000030948 OR RCV000033333 OR RCV000208539 OR RCV000505705 OR RCV001813207 OR RCV002271369 OR RCV002513056" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015003, RCV000030948, RCV000033333, RCV000208539, RCV000505705, RCV001813207, RCV002271369, RCV002513056" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015003...</a>
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<p>In patient with Noonan syndrome-7 (NS7; <a href="/entry/613706">613706</a>), <a href="#73" class="mim-tip-reference" title="Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others. <strong>Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.</strong> Hum. Mutat. 30: 695-702, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19206169[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206169">Sarkozy et al. (2009)</a> identified a heterozygous de novo 1789C-G transversion in exon 15 of the BRAF gene, resulting in a leu597-to-val (L597V) substitution. In vitro functional expression studies showed that the W531C mutant protein did not show transforming ability to cells in vitro, although there was a slight increase in MEK phosphorylation, suggesting activation of the downstream MAPK pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0027 LEOPARD SYNDROME 3</strong>
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BRAF, LEU245PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397507466 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397507466;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397507466?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397507466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397507466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033283 OR RCV000037956 OR RCV000171142 OR RCV000469440 OR RCV000515291 OR RCV000788013" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033283, RCV000037956, RCV000171142, RCV000469440, RCV000515291, RCV000788013" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033283...</a>
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<p>In a 17-year-old Czech boy with LEOPARD syndrome-3 (LPRD3; <a href="/entry/613707">613707</a>), <a href="#38" class="mim-tip-reference" title="Koudova, M., Seemanova, E., Zenker, M. <strong>Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence.</strong> Europ. J. Med. Genet. 52: 337-340, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19416762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19416762</a>] [<a href="https://doi.org/10.1016/j.ejmg.2009.04.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19416762">Koudova et al. (2009)</a> identified a de novo heterozygous c.735A-G transition in exon 6 of the BRAF gene, resulting in a leu245-to-phe (L245F) substitution at a highly conserved residue. The mutation was not found in more than 300 controls, and functional studies were not performed. Notably, the patient did not have cognitive impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19416762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<ol>
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<a id="1" class="mim-anchor"></a>
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<a id="Ball2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ball, D. W., Jin, N., Rosen, D. M., Dackiw, A., Sidransky, D., Xing, M., Nelkin, B. D.
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<strong>Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244.</strong>
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J. Clin. Endocr. Metab. 92: 4712-4718, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17878251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17878251</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17878251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2007-1184" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
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<a id="Bollag2010" class="mim-anchor"></a>
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<div class="">
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Bollag, G., Hirth, P., Tsai, J., Zhang, J., Ibrahim, P. N., Cho, H., Spevak, W., Zhang, C., Zhang, Y., Habets, G., Burton, E. A., Wong, B., and 28 others.
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<strong>Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.</strong>
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Nature 467: 596-599, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20823850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20823850</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20823850[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20823850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature09454" target="_blank">Full Text</a>]
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<a id="Boussemart2014" class="mim-anchor"></a>
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<div class="">
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Boussemart, L., Malka-Mahieu, H., Girault, I., Allard, D., Hemmingsson, O., Tomasic, G., Thomas, M., Basmadjian, C., Ribeiro, N., Thuaud, F., Mateus, C., Routier, E., Kamsu-Kom, N., Agoussi, S., Eggermont, A. M., Desaubry, L., Robert, C., Vagner, S.
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<strong>eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.</strong>
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Nature 513: 105-109, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25079330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25079330</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25079330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature13572" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Brady2014" class="mim-anchor"></a>
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<div class="">
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Brady, D. C., Crowe, M. S., Turski, M. L., Hobbs, G. A., Yao, X., Chaikuad, A., Knapp, S., Xiao, K., Campbell, S. L., Thiele, D. J., Counter, C. M.
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<strong>Copper is required for oncogenic BRAF signalling and tumorigenesis.</strong>
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Nature 509: 492-496, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24717435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24717435</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24717435[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24717435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature13180" target="_blank">Full Text</a>]
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<a id="Brose2002" class="mim-anchor"></a>
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<div class="">
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Brose, M. S., Volpe, P., Feldman, M., Kumar, M., Rishi, I., Gerrero, R., Einhorn, E., Herlyn, M., Minna, J., Nicholson, A., Roth, J. A., Albelda, S. M., Davies, H., Cox, C., Brignell, G., Stephens, P., Futreal, P. A., Wooster, R., Stratton, M. R., Weber, B. L.
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<strong>BRAF and RAS mutations in human lung cancer and melanoma.</strong>
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Cancer Res. 62: 6997-7000, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12460918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12460918</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12460918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Chapman2009" class="mim-anchor"></a>
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Chapman, P., Puzanov, I., sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R., Grippo, J., Nolop, K., Flaherty, K.
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<strong>Early efficacy signal demonstrated in advanced melanoma in a phase I trial of the oncogenic BRAF-selective inhibitor PLX4032. (Abstract)</strong>
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Europ. J. Cancer Suppl. 7: 5 only, 2009.
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<a id="7" class="mim-anchor"></a>
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<a id="Ciampi2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ciampi, R., Knauf, J. A., Kerler, R., Gandhi, M., Zhu, Z., Nikiforova, M. N., Rabes, H. M., Fagin, J. A., Nikiforov, Y. E.
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<strong>Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer.</strong>
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J. Clin. Invest. 115: 94-101, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15630448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15630448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15630448[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15630448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI23237" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Curtin2005" class="mim-anchor"></a>
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Curtin, J. A., Fridlyand, J., Kageshita, T., Patel, H. N., Busam, K. J., Kutzner, H., Cho, K.-H., Aiba, S., Brocker, E.-B., LeBoit, P. E., Pinkel, D., Bastian, B. C.
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<strong>Distinct sets of genetic alterations in melanoma.</strong>
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New Eng. J. Med. 353: 2135-2147, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16291983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16291983</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16291983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa050092" target="_blank">Full Text</a>]
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<a id="Dankort2009" class="mim-anchor"></a>
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Dankort, D., Curley, D. P., Cartlidge, R. A., Nelson, B., Karnezis, A. N., Damsky, W. E., Jr., You, M. J., DePinho, R. A., McMahon, M., Bosenberg, M.
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<strong>Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.</strong>
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Nature Genet. 41: 544-552, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19282848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19282848</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19282848[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19282848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.356" target="_blank">Full Text</a>]
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<a id="Davies2002" class="mim-anchor"></a>
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Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., Davis, N., Dicks, E., and 40 others.
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<strong>Mutations of the BRAF gene in human cancer.</strong>
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Nature 417: 949-954, 2002.
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[<a href="https://doi.org/10.1038/nature00766" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/cncr.20861" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.020651" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2006-2707" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.bjc.6600919" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2003.016667" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1002011" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ccr.2004.09.022" target="_blank">Full Text</a>]
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Xing, M., Tufano, R. P., Tufaro, A. P., Basaria, S., Ewertz, M., Rosenbaum, E., Byrne, P. J., Wang, J., Sidransky, D., Ladenson, P. W.
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<strong>Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15181070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15181070</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15181070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2003-032050" target="_blank">Full Text</a>]
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Xing, M., Vasko, V., Tallini, G., Larin, A., Wu, G., Udelsman, R., Ringel, M. D., Ladenson, P. W., Sidransky, D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15001635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15001635</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15001635" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2003-031488" target="_blank">Full Text</a>]
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Xing, M., Westra, W. H., Tufano, R. P., Cohen, Y., Rosenbaum, E., Rhoden, K. J., Carson, K. A., Vasko, V., Larin, A., Tallini, G., Tolaney, S., Holt, E. H., and 10 others.
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J. Clin. Endocr. Metab. 90: 6373-6379, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16174717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16174717</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16174717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2005-0987" target="_blank">Full Text</a>]
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Yao, Z., Yaeger, R., Rodrik-Outmezguine, V. S., Tao, A., Torres, N. M., Chang, M. T., Drosten, M., Zhao, H., Cecchi, F., Hembrough, T., Michels, J., Baumert, H., Miles, L., Campbell, N. M., de Stanchina, E., Solit, D. B., Barbacid, M., Taylor, B. S., Rosen, N.
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<strong>Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.</strong>
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Nature 548: 234-238, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28783719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28783719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28783719[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28783719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature23291" target="_blank">Full Text</a>]
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Yu, J., Deshmukh, H., Gutmann, R. J., Emnett, R. J., Rodriguez, F. J., Watson, M. A., Nagarajan, R., Gutmann, D. H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19794125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19794125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19794125[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19794125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181c0664a" target="_blank">Full Text</a>]
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Yuasa, Y., Kamiyama, T., Kato, M., Iwama, T., Ikeuchi, T., Tonomura, A.
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Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., Roper, J., Chio, I. I. C., Giannopoulou, E. G., Rago, C., Muley, A., Asara, J. M., Paik, J., Elemento, O., Chen, Z., Pappin, D. J., Dow, L. E., Papadopoulos, N., Gross, S. S., Cantley, L. C.
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<strong>Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.</strong>
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Science 350: 1391-1396, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26541605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26541605</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26541605[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26541605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aaa5004" target="_blank">Full Text</a>]
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Zhong, S., Delva, L., Rachez, C., Cenciarelli, C., Gandini, D., Zhang, H., Kalantry, S., Freedman, L. P., Pandolfi, P. P.
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<strong>A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RAR-alpha and T18 oncoproteins.</strong>
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Nature Genet. 23: 287-295, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10610177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10610177</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10610177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/15463" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 03/16/2020
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Bao Lige - updated : 01/07/2020<br>Ada Hamosh - updated : 08/06/2018<br>Ada Hamosh - updated : 01/31/2018<br>Ada Hamosh - updated : 01/18/2018<br>Marla J. F. O'Neill - updated : 09/02/2016<br>Ada Hamosh - updated : 02/17/2016<br>Patricia A. Hartz - updated : 8/17/2015<br>Cassandra L. Kniffin - updated : 5/13/2015<br>Patricia A. Hartz - updated : 3/17/2015<br>Ada Hamosh - updated : 10/3/2014<br>Ada Hamosh - updated : 8/25/2014<br>Ada Hamosh - updated : 7/16/2014<br>Ada Hamosh - updated : 5/21/2014<br>Ada Hamosh - updated : 8/27/2013<br>Ada Hamosh - updated : 2/26/2013<br>Ada Hamosh - updated : 8/29/2012<br>Ada Hamosh - updated : 2/27/2012<br>Marla J. F. O'Neill - updated : 11/29/2011<br>Cassandra L. Kniffin - updated : 4/14/2011<br>Ada Hamosh - updated : 2/9/2011<br>Cassandra L. Kniffin - updated : 1/21/2011<br>Ada Hamosh - updated : 10/12/2010<br>Cassandra L. Kniffin - updated : 10/5/2010<br>Patricia A. Hartz - updated : 5/19/2010<br>Patricia A. Hartz - updated : 5/11/2010<br>Ada Hamosh - updated : 4/15/2010<br>Patricia A. Hartz - updated : 4/7/2010<br>Ada Hamosh - updated : 10/19/2009<br>Ada Hamosh - updated : 10/2/2009<br>Marla J. F. O'Neill - updated : 9/10/2009<br>Cassandra L. Kniffin - updated : 7/8/2009<br>Ada Hamosh - updated : 6/16/2009<br>John A. Phillips, III - updated : 3/9/2009<br>John A. Phillips, III - updated : 3/9/2009<br>John A. Phillips, III - updated : 1/14/2009<br>Jane Kelly - updated : 7/3/2008<br>John A. Phillips, III - updated : 5/28/2008<br>Cassandra L. Kniffin - updated : 5/15/2008<br>Cassandra L. Kniffin - updated : 3/17/2008<br>John A. Phillips, III - updated : 1/7/2008<br>John A. Phillips, III - updated : 4/10/2007<br>John A. Phillips, III - updated : 3/21/2007<br>Marla J. F. O'Neill - updated : 9/26/2006<br>Ada Hamosh - updated : 8/11/2006<br>Victor A. McKusick - updated : 6/30/2006<br>Ada Hamosh - updated : 6/8/2006<br>Ada Hamosh - updated : 4/19/2006<br>John A. Phillips, III - updated : 4/14/2006<br>John A. Phillips, III - updated : 4/4/2006<br>Victor A. McKusick - updated : 2/24/2006<br>Victor A. McKusick - updated : 12/1/2005<br>Marla J. F. O'Neill - updated : 10/11/2005<br>Ada Hamosh - updated : 9/7/2005<br>John A. Phillips, III - updated : 7/26/2005<br>John A. Phillips, III - updated : 7/11/2005<br>Victor A. McKusick - updated : 6/3/2005<br>John A. Phillips, III - updated : 4/26/2005<br>John A. Phillips, III - updated : 4/12/2005<br>John A. Phillips, III - updated : 3/31/2005<br>Marla J. F. O'Neill - updated : 2/2/2005<br>Victor A. McKusick - updated : 10/12/2004<br>Victor A. McKusick - updated : 4/29/2004<br>Victor A. McKusick - updated : 4/22/2004<br>Stylianos E. Antonarakis - updated : 4/13/2004<br>Victor A. McKusick - updated : 1/20/2004<br>Victor A. McKusick - updated : 9/2/2003<br>Victor A. McKusick - updated : 4/16/2003<br>Victor A. McKusick - updated : 3/3/2003<br>Ada Hamosh - updated : 9/17/2002<br>Ada Hamosh - updated : 7/10/2002<br>Ada Hamosh - updated : 11/3/1999<br>Victor A. McKusick - updated : 7/3/1997
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Victor A. McKusick : 12/1/1992
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alopez : 03/16/2020<br>carol : 01/28/2020<br>mgross : 01/07/2020<br>carol : 06/13/2019<br>carol : 09/12/2018<br>carol : 08/21/2018<br>carol : 08/20/2018<br>alopez : 08/06/2018<br>alopez : 01/31/2018<br>alopez : 01/18/2018<br>carol : 09/02/2016<br>alopez : 08/04/2016<br>alopez : 02/17/2016<br>carol : 9/9/2015<br>mgross : 8/17/2015<br>mgross : 8/17/2015<br>carol : 5/27/2015<br>mcolton : 5/14/2015<br>ckniffin : 5/13/2015<br>carol : 4/9/2015<br>mgross : 3/26/2015<br>mcolton : 3/17/2015<br>alopez : 3/11/2015<br>carol : 11/14/2014<br>alopez : 10/3/2014<br>alopez : 8/25/2014<br>alopez : 7/16/2014<br>alopez : 5/21/2014<br>mgross : 10/25/2013<br>alopez : 8/27/2013<br>alopez : 6/20/2013<br>alopez : 3/4/2013<br>terry : 2/26/2013<br>alopez : 9/5/2012<br>terry : 8/29/2012<br>terry : 8/29/2012<br>alopez : 3/2/2012<br>terry : 2/27/2012<br>carol : 11/29/2011<br>carol : 9/13/2011<br>wwang : 4/25/2011<br>ckniffin : 4/14/2011<br>alopez : 2/9/2011<br>terry : 2/8/2011<br>wwang : 2/7/2011<br>ckniffin : 1/21/2011<br>alopez : 10/12/2010<br>alopez : 10/12/2010<br>terry : 10/12/2010<br>wwang : 10/5/2010<br>ckniffin : 10/5/2010<br>carol : 7/16/2010<br>mgross : 5/20/2010<br>terry : 5/19/2010<br>mgross : 5/11/2010<br>mgross : 5/11/2010<br>terry : 5/11/2010<br>alopez : 4/20/2010<br>terry : 4/15/2010<br>mgross : 4/7/2010<br>terry : 4/7/2010<br>wwang : 10/28/2009<br>alopez : 10/26/2009<br>terry : 10/19/2009<br>alopez : 10/7/2009<br>terry : 10/2/2009<br>wwang : 9/29/2009<br>terry : 9/10/2009<br>wwang : 8/3/2009<br>ckniffin : 7/8/2009<br>alopez : 6/17/2009<br>terry : 6/16/2009<br>alopez : 3/9/2009<br>alopez : 3/9/2009<br>alopez : 1/14/2009<br>carol : 12/4/2008<br>carol : 7/3/2008<br>carol : 5/28/2008<br>wwang : 5/19/2008<br>ckniffin : 5/15/2008<br>wwang : 3/19/2008<br>ckniffin : 3/17/2008<br>carol : 1/7/2008<br>wwang : 10/4/2007<br>carol : 9/6/2007<br>carol : 4/10/2007<br>carol : 3/22/2007<br>carol : 3/21/2007<br>terry : 11/3/2006<br>wwang : 9/27/2006<br>terry : 9/26/2006<br>terry : 8/25/2006<br>carol : 8/11/2006<br>terry : 8/11/2006<br>alopez : 7/5/2006<br>terry : 6/30/2006<br>alopez : 6/8/2006<br>alopez : 6/8/2006<br>terry : 4/19/2006<br>alopez : 4/14/2006<br>alopez : 4/4/2006<br>alopez : 3/3/2006<br>terry : 2/24/2006<br>alopez : 12/6/2005<br>alopez : 12/6/2005<br>terry : 12/1/2005<br>terry : 11/10/2005<br>wwang : 10/14/2005<br>terry : 10/11/2005<br>alopez : 9/14/2005<br>terry : 9/7/2005<br>alopez : 7/26/2005<br>alopez : 7/11/2005<br>terry : 6/28/2005<br>alopez : 6/14/2005<br>terry : 6/3/2005<br>alopez : 4/26/2005<br>mgross : 4/14/2005<br>alopez : 4/12/2005<br>alopez : 3/31/2005<br>tkritzer : 2/3/2005<br>terry : 2/2/2005<br>tkritzer : 10/14/2004<br>terry : 10/12/2004<br>tkritzer : 5/3/2004<br>terry : 4/29/2004<br>tkritzer : 4/22/2004<br>terry : 4/22/2004<br>mgross : 4/13/2004<br>cwells : 1/22/2004<br>terry : 1/20/2004<br>tkritzer : 12/16/2003<br>terry : 12/9/2003<br>cwells : 9/4/2003<br>terry : 9/2/2003<br>carol : 4/17/2003<br>terry : 4/16/2003<br>carol : 3/11/2003<br>tkritzer : 3/10/2003<br>tkritzer : 3/10/2003<br>terry : 3/3/2003<br>alopez : 1/2/2003<br>alopez : 12/9/2002<br>terry : 12/6/2002<br>alopez : 9/17/2002<br>alopez : 7/11/2002<br>terry : 7/10/2002<br>alopez : 11/3/1999<br>mark : 7/8/1997<br>terry : 7/3/1997<br>mark : 6/9/1996<br>terry : 5/11/1994<br>carol : 5/27/1993<br>carol : 4/7/1993<br>carol : 1/4/1993<br>carol : 12/23/1992<br>carol : 12/1/1992
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 164757
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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B-RAF PROTOONCOGENE, SERINE/THREONINE KINASE; BRAF
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1<br />
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ONCOGENE BRAF<br />
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BRAF1<br />
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RAFB1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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BRAF/AKAP9 FUSION GENE, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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BRAF/KIAA1549 FUSION GENE, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: BRAF</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 403770008;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 7q34
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:140,713,328-140,924,929 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="7">
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<span class="mim-font">
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7q34
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</span>
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</td>
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<td>
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<span class="mim-font">
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Adenocarcinoma of lung, somatic
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</span>
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</td>
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<td>
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<span class="mim-font">
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211980
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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|
3
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Cardiofaciocutaneous syndrome
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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115150
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Autosomal dominant
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</span>
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</td>
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<td>
|
|
<span class="mim-font">
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|
3
|
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</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
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<span class="mim-font">
|
|
Colorectal cancer, somatic
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
114500
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
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<span class="mim-font">
|
|
LEOPARD syndrome 3
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
613707
|
|
</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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3
|
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</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Melanoma, malignant, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
155600
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Nonsmall cell lung cancer, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
211980
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Noonan syndrome 7
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613706
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
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<div>
|
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|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
<span class="mim-text-font">
|
|
<p>Using an oligomer unique to the BRAF kinase domain, Sithanandam et al. (1990) cloned full-length BRAF from a testis cDNA library. The deduced 651-amino acid protein has a calculated molecular mass of 72.5 kD. It contains all 3 conserved regions of RAF protein kinases: a putative zinc finger region, a serine/threonine-rich region, and a C-terminal kinase domain, which includes a putative ATP-binding site and a catalytic lysine. In addition, the N terminus of BRAF is serine-rich, and it has a consensus CDC2 (CDK1; 116940) phosphorylation motif. Northern blot analysis detected transcripts of 10 and 13 kb in cerebrum, fetal brain, and placenta and transcripts of 2.6 and 4.5 kb in testis. Testis also showed lower expression of the 10- and 13-kb transcripts. </p><p>Eychene et al. (1992) stated that the BRAF gene is the human homolog of the avian c-Rmil protooncogene encoding a 94-kD serine/threonine kinase detected in avian cells. This protein contains amino-terminal sequences not found in other proteins of the mil/raf gene family. These sequences are encoded by 3 exons in the avian genome. Eychene et al. (1992) reported that these 3 exons are conserved in the human BRAF gene and that they encode an amino acid sequence similar to that of the avian gene. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Fusion of PML (102578) and TIF1A (603406) to RARA (180240) and BRAF, respectively, results in the production of PML-RAR-alpha and TIF1-alpha-B-RAF (T18) oncoproteins. Zhong et al. (1999) showed that PML, TIF1-alpha, and RXR-alpha (180245)/RAR-alpha function together in a retinoic acid-dependent transcription complex. PML interacts with TIF1-alpha and CREB-binding protein (CBP; 600140). T18, similar to PML-RAR-alpha, disrupts the retinoic acid-dependent activity of this complex in a dominant-negative manner, resulting in a growth advantage. </p><p>Using a genomewide RNA interference screen, Wajapeyee et al. (2008) identified 17 factors required for oncogenic BRAF to induce senescence in primary fibroblasts and melanocytes. One of these factors is an F-box protein, FBXO31 (609102), a candidate tumor suppressor encoded in 16q24.3, a region in which there is loss of heterozygosity in breast, ovarian, hepatocellular, and prostate cancers. Santra et al. (2009) studied the cellular role of FBXO31, identified its target substrate, and determined the basis for its growth inhibitory activity. They showed that ectopic expression of FBXO31 acts through a proteasome-directed pathway to mediate the degradation of cyclin D1 (168461), an important regulator of progression from G1 to S phase, resulting in arrest in G1. Cyclin D1 degradation results from a direct interaction with FBXO31 and is dependent on the F-box motif of FBXO31 and phosphorylation of cyclin D1 at thr286, which is required for cyclin D1 proteolysis. The involvement of the DNA damage response in oncogene-induced senescence prompted Santra et al. (2009) to investigate the role of FBXO31 in DNA repair. They found that DNA damage induced by gamma-irradiation results in increased FBXO31 levels, which requires phosphorylation of FBXO31 by the DNA damage response-initiating kinase ATM (607585). RNAi-mediated knockdown of FBXO31 prevents cells from undergoing efficient arrest in G1 after gamma-irradiation and markedly increases sensitivity to DNA damage. Finally, Santra et al. (2009) showed that a variety of DNA damaging agents all result in a large increase in FBXO31 levels, indicating that induction of FBXO31 is a general response to genotoxic stress. Santra et al. (2009) concluded that their results reveal FBXO31 as a regulator of the G1/S transition that is specifically required for DNA damage-induced growth arrest. </p><p>Using Drosophila Schneider S2 cells, Rajakulendran et al. (2009) demonstrated that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which they termed the side-to-side dimer. Rajakulendran et al. (2009) also showed that RAF side-to-side dimer formation is essential for aberrant signaling by oncogenic BRAF mutants, and identified an oncogenic mutation (G558K, Davies et al., 2002) that acts specifically by promoting side-to-side dimerization. Rajakulendran et al. (2009) concluded that their data identified the side-to-side dimer interface of RAF as a potential therapeutic target for intervention in BRAF-dependent tumorigenesis. </p><p>To investigate how ultraviolet radiation (UVR) accelerates oncogenic BRAF-driven melanomagenesis (CMM1; 155600), Viros et al. (2014) used a BRAF mutant (V600E; 164757.0001) mouse model. In mice expressing the V600E mutation in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. Viros et al. (2014) showed that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma but provided only partial protection. The UVR-exposed tumors showed increased numbers of single-nucleotide variants, and Viros et al. (2014) observed mutations in Trp53 (TP53; 191170) in approximately 40% of cases. TP53 is an accepted UVR target in human nonmelanoma skin cancer but was not thought to play a major role in melanoma. However, Viros et al. (2014) showed that in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that in humans TP53 mutations are linked to evidence of UVR-induced DNA damage in melanoma. Thus, the authors provided mechanistic insight into epidemiologic data linking UVR to acquired nevi in humans. Furthermore, they identified TP53/Trp53 as a UVR target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Viros et al. (2014) stated that their study validated public health campaigns that promote sunscreen protection for individuals at risk of melanoma. </p><p>Karreth et al. (2015) noted that pseudogenes have the potential to posttranscriptionally regulate their parental transcripts. They found that the human and mouse BRAF pseudogenes, BRAFP1 (300956) and Brafrs1, respectively, increased expression of BRAF and phosphorylated ERK and stimulated proliferation in human and mouse cells. In vitro, BRAFP1 and Brafrs1 upregulated BRAF expression and BRAF signaling by acting as decoys that sequestered microRNAs (miRNAs) shared between BRAF and its pseudogenes, thus relieving miRNA-dependent BRAF repression. </p><p>Yun et al. (2015) found that cultured human colorectal cancer cells harboring KRAS (190070) or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 (138140) glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wildtype cells. High-dose vitamin C impairs tumor growth in Apc/Kras(G12D) mutant mice. Yun et al. (2015) suggested that their results provided a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations. </p><p><strong><em>MEK Inhibition</em></strong></p><p>
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Using small-molecule inhibitors of MAPK/ERK kinase (MEK; see 176872) and an integrated genetic and pharmacologic analysis, Solit et al. (2006) found that mutation of BRAF is associated with enhanced and selective sensitivity to MEK inhibition when compared to either wildtype cells or cells harboring a RAS mutation. This MEK dependency was observed in BRAF mutant cells regardless of tissue lineage, and correlated with both downregulation of cyclin D1 (168461) protein expression and the induction of G1 arrest. Pharmacologic MEK inhibition completely abrogated tumor growth in BRAF mutant xenografts, whereas RAS (see 190020) mutant tumors were only partially inhibited. Solit et al. (2006) concluded that their data suggested an exquisite dependency on MEK activity in BRAF mutant tumors. </p><p>Ball et al. (2007) examined MEK inhibition and cell growth in 4 BRAF mutant (V600E; 164757.0001) and 2 BRAF wildtype thyroid cancer cell lines and in xenografts from a BRAF mutant cell line after treatment with the potent MEK1/2 inhibitor AZD6244. AZD6244 potently inhibited MEK1/2 activity in thyroid cancer cell lines regardless of BRAF mutation status. Ball et al. (2007) concluded that AZD6244 inhibits the MEK-ERK pathway across a spectrum of thyroid cancer cells. MEK inhibition is cytostatic in papillary thyroid cancer and anaplastic thyroid cancer cells bearing a BRAF mutation and may have less impact on thyroid cancer cells lacking this mutation. </p><p>Leboeuf et al. (2008) investigated whether sensitivity to MEK inhibition was determined by oncogene status in 13 human thyroid cancer cell lines: 4 with mutation in BRAF, 4 with mutation in RAS, 1 carrying RET/PTC1 (see 601985), and 4 wildtype. Thyroid cancers with BRAF mutation were preferentially sensitive to MEK inhibitors, whereas tumors with other MEK-ERK effector pathway gene mutations had variable responses, either because they were only partially dependent on ERK and/or because feedback responses elicited partial refractoriness to MEK inhibition. </p><p>Poulikakos et al. (2010) used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for the paradoxical activation of the enzyme by inhibitors. Induction of ERK signaling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF-CRAF) or heterodimers (CRAF-BRAF) inhibits one promoter, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumors, RAS is not activated, thus transactivation is minimal and ERK signaling is inhibited in cells exposed to RAF inhibitors. These results indicated that RAF inhibitors will be effective in tumors in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signaling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumor activity than MEK inhibitors, but could also cause toxicity due to the MEK/ERK activation. Poulikakos et al. (2010) noted that these predictions were borne out in a clinical trial of the RAF inhibitor PLX4032, as reported by Chapman et al. (2009) and Flaherty et al. (2009). The model indicated that promotion of RAF dimerization by elevation of wildtype RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumors. In agreement with this prediction, RAF inhibitors do not inhibit ERK signaling in cells that coexpress BRAF(V600E) and mutant RAS. </p><p>Hatzivassiliou et al. (2010) demonstrated that ATP-competitive RAF inhibitors have 2 opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumors, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signaling pathway and decrease tumor growth. Notably, in KRAS mutant and RAS/RAF wildtype tumors, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumor growth in some xenograft models. Inhibitor binding activates wildtype RAF isoforms by inducing dimerization, membrane localization, and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, Hatzivassiliou et al. (2010) demonstrated that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signaling pathways, depending on the cellular context. The authors stated that their work provided new insights into the therapeutic use of ATP-competitive RAF inhibitors. </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Park et al. (2019) used cryoelectron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 (176872) and a 14-3-3 dimer of eta (YWHAH; 113508) and zeta (YWHAZ; 601288). The reconstruction revealed an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of 2 BRAFs, which drives the formation of an active, back-to-back BRAF dimer. </p>
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<strong>Mapping</strong>
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<p>Eychene et al. (1992) identified 2 human BRAF loci: BRAF1, which was mapped to 7q34 by fluorescence in situ hybridization and shown to encode the functional gene product, and BRAF2, an inactive processed pseudogene located on Xq13. Sithanandam et al. (1992) mapped the BRAF gene to the same region by Southern blot analysis of rodent/human somatic cell hybrids and by in situ hybridization, but concluded that the pseudogene is located near the active gene. Using a single interspecific backcross, Justice et al. (1990) demonstrated that the mouse Braf gene is located on chromosome 10. </p><p>Yuasa et al. (1990) searched for oncogenes associated with familial adenomatous polyposis by a tumorigenicity assay in nude mice. In the course of these studies, a transforming sequence was isolated that did not hybridize with 12 known oncogene probes. It was partially cloned and shown to be located on human chromosome 7. The gene did not hybridize with the MET (164860) and ERBB1 (131550) oncogenes which are located on chromosome 7. By sequence analysis of cDNA clones presumably containing the transforming gene, Kamiyama et al. (1993) showed that the sequence contained an activated BRAF, the 5-prime half of which was replaced by the SNRPE gene and an unknown gene. Analysis indicated that rearrangements had occurred during transfection. By Southern blot analysis of rodent-human somatic cell hybrid analysis, Kamiyama et al. (1993) mapped the BRAF gene to chromosome 7. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Somatic Mutations in Various Cancers</em></strong></p><p>
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Davies et al. (2002) identified BRAF somatic missense mutations in 66% of malignant melanomas (see 155600) and at lower frequency in a wide range of human cancers. All mutations were within the kinase domain, with a single substitution, V600E (164757.0001), originally reported as V599E, accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH 3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V600E mutation. Davies et al. (2002) suggested that since BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma. Presumptive BRAF mutations were identified in 43 cancer cell lines including 20 of 34 (59%) melanomas, 7 of 40 (18%) colorectal cancers, 4 of 38 (11%) gliomas, 4 of 131 (3%) lung cancers, 5 of 59 (9%) sarcomas, 1 of 26 (4%) ovarian carcinomas, 1 of 45 (2%) breast cancers, and 1 of 7 (14%) liver cancers. Mutations were not found in cancer cell lines derived from 29 neuroblastomas, 10 bladder cancers, 53 leukemia/lymphomas, 11 cervical carcinomas, 11 renal cell carcinomas, 3 pancreatic carcinomas, 3 prostate carcinomas, 6 gastric carcinomas, 7 testicular carcinomas, 3 uterine carcinomas, and 29 other cancers. </p><p>Rajagopalan et al. (2002) systematically evaluated mutation in BRAF and KRAS (190070) in 330 colorectal tumors (see 114500). There were 32 mutations in BRAF, 28 with a V600E mutation and 1 each with the R462I (164757.0002), I463S (164757.0003), G464E (164757.0004), or K601E (164757.0005) mutations. All but 2 mutations seemed to be heterozygous, and in all 20 cases for which normal tissue was available, the mutations were shown to be somatic. In the same set of tumors there were 169 mutations in KRAS. No tumor exhibited mutations in both BRAF and KRAS. There was also a striking difference in the frequency of BRAF mutations between cancers with and without mismatch repair deficiency. The V600E mutation was identified in all but 1 of the 15 mismatch repair deficient cases. Rajagopalan et al. (2002) concluded their results provide strong support for the hypothesis that BRAF and KRAS mutations are equivalent in their tumorigenic effects. Both genes seem to be mutated at a similar phase of tumorigenesis, after initiation but before malignant conversion. Moreover, no tumor concurrently contained both BRAF and KRAS mutations. </p><p>Kim et al. (2003) stated that the most common BRAF mutation, V600E, had not been identified in tumors with mutations in the KRAS gene. They studied the incidence of BRAF mutations in gastric cancers and the relationship between BRAF and KRAS mutations in these cancers. They found 7 KRAS missense mutations in 66 gastric cancers and 16 gastric cancer cell lines. No BRAF mutations were found. </p><p>Namba et al. (2003) determined the frequency of BRAF mutations in thyroid cancer and their correlation with clinicopathologic parameters. The V600E mutation was found in 4 of 6 cell lines and 51 of 207 thyroid tumors (24.6%). Examination of 126 patients with papillary thyroid cancer showed that BRAF mutation correlated significantly with distant metastasis (P = 0.033) and clinical stage (P = 0.049). The authors concluded that activating mutation in the BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers. </p><p>Giannini et al. (2007) examined the pattern of BRAF mutations in noncontiguous tumor foci and node metastases from 69 patients affected by multicentric PTC. Discordant patterns of BRAF mutation were found in about 40% of the multifocal PTCs. In node metastases, BRAF mutations were, in most but not all the cases, concordant with the dominant tumor. A discordant pattern of BRAF mutation was also found in about 50% of the cases in which multiple foci of different histopathologic variants were present. Giannini et al. (2007) concluded that the heterogeneous distribution of BRAF mutations suggests that discrete tumor foci in multifocal PTC may occur as independent tumors. </p><p>Brose et al. (2002) identified BRAF mutations in 5 of 179 nonsmall cell lung cancers (NSCLCs) and in 22 of 35 melanomas. Although more than 90% of previously identified BRAF mutations in melanoma involved codon 599, 8 of 9 in NSCLC were non-V600, strongly suggesting that BRAF mutations in NSCLC are qualitatively different from those in melanoma; thus, there may be therapeutic differences between lung cancer and melanoma in response to RAF inhibitors. Although uncommon, BRAF mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy. </p><p>The discovery of activating mutations in the BRAF gene in many cutaneous melanomas prompted Edmunds et al. (2003) to screen the genomic sequence of BRAF exons 11 and 15 in a series of 48 intraocular (uveal) melanomas (155720), together with control samples from 3 cutaneous melanomas and a melanoma cell line that has a BRAF mutation. The same mutation was detected in two-thirds of the cutaneous samples, but was not present in any uveal melanomas. The finding further underlined the distinction between uveal and cutaneous melanomas, and suggested that BRAF inhibitors are unlikely to benefit patients with uveal melanoma. </p><p>Using the very sensitive pyrophosphorolysis-activated polymerization (PAP) assay to screen for mutations in exon 15 of the BRAF gene in 11 uveal melanoma cell lines and 45 primary uveal melanomas, Maat et al. (2008) identified mutations in 2 cell lines (V600E; 164757.0001) and 6 primary tumors. Direct sequencing of the exon 15 PCR product did not reveal the mutations found with the PAP assay, indicating a low frequency of the mutant allele in primary samples. Maat et al. (2008) concluded that the relative scarcity of the BRAF mutations excluded an elemental role for them in uveal melanoma. </p><p>Wan et al. (2004) analyzed 22 BRAF mutants and found that 18 had elevated kinase activity and signaled to ERK (see 601795) in vivo. Three mutants had reduced kinase activity towards MEK (see 176872) in vitro but, by activating CRAF (164760) in vivo, signaled to ERK in cells. The structures of wildtype and oncogenic V600E mutant BRAF kinase domains in complex with a RAF inhibitor showed that the activation segment is held in an inactive conformation by association with the P loop. The authors stated that the clustering of most mutations to these 2 regions suggests that disruption of this interaction converts BRAF into its active conformation. The high-activity mutants signaled to ERK by directly phosphorylating MEK, whereas the impaired-activity mutants stimulated MEK by activating endogenous CRAF. </p><p>Ciampi et al. (2005) reported a rearrangement of BRAF via paracentric inversion of chromosome 7q, resulting in an in-frame fusion between exons 1-8 of the AKAP9 gene (604001) and exons 9-18 of BRAF. The fusion protein contained the protein kinase domain and lacked the autoinhibitory N-terminal portion of BRAF. It had elevated kinase activity and transformed NIH 3T3 cells. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas developing after a short latency, whereas BRAF point mutations (see 164757.0001) were absent in this group. Ciampi et al. (2005) concluded that in thyroid cancer, radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions, whereas in sporadic forms of the disease, effectors along the same pathway are activated predominantly by point mutations. </p><p>Oncogenic mutations in the DNA sequence encoding the kinase domain of BRAF are found in most primary cell lines derived from cutaneous melanomas (Davies et al., 2002; Brose et al., 2002). Approximately 90% of these mutations in melanomas are due to a recurrent 1799T-A transversion in exon 15 of the BRAF gene, resulting in a V600E mutation (164757.0001), suggesting that a specific environmental exposure contributes to the genesis of this mutation; however, the common 1799T-A BRAF mutation is not a characteristic ultraviolet signature mutation. Edwards et al. (2004) studied the BRAF gene in melanomas arising in sites protected from sun exposure. None of 13 mucosal melanomas had a mutation in exon 15 of the BRAF gene, as compared to 54 of 165 (33%) primary cutaneous melanomas in a compilation of all previously published studies. The data suggested that UV exposure plays a role in the genesis of BRAF mutations in cutaneous melanomas, despite the absence of the characteristic C-to-T or CC-to-TT mutation signature associated with UV exposure, and suggested mechanisms other than pyrimidine dimer formation as important in UV-induced mutagenesis. </p><p>Landi et al. (2006) showed that MC1R (155555) variants are strongly associated with BRAF mutations in nonchronic sun-induced damage melanomas. In this tumor subtype, the risk for melanoma associated with MC1R is due to an increase in risk of developing melanomas with BRAF mutations. Landi et al. (2006) found that BRAF mutations were more frequent in nonchronic sun-induced damage melanoma cases with germline MC1R variants than in those with 2 wildtype MC1R alleles. When the authors categorized patients into 2 groups, homozygous MC1R wildtype versus all others, they found that BRAF mutations were 6 to 13 times as frequent in those with at least 1 MC1R variant allele compared to those with no MC1R variants. Four more tests for interaction between age and MC1R were not significant. Comparison of nonchronic sun-damaged Italian cases with 171 healthy Italian controls showed that the overall melanoma risk was higher by a factor of 3.3 (95% CI 1.5-6.9) in individuals with any MC1R variant allele compared to individuals with no variant alleles and that the risk increased with the number of variant MC1R alleles. </p><p>Desmoplastic melanoma is an uncommon variant of cutaneous melanoma that mimics soft tissue sarcoma both clinically and morphologically. An activating point mutation in the BRAF oncogene has been identified in a high proportion of conventional cutaneous melanomas, but Davison et al. (2005) showed that the desmoplastic variant frequency does not harbor such a mutation. Accordingly, patients with melanomas should not be collectively regarded as a uniform group as new therapeutic strategies are developed that target specific genetic alterations. They found the V600E mutation in 23 of 57 conventional cutaneous melanoma specimens but in none of 12 desmoplastic melanoma specimens. </p><p>Michaloglou et al. (2005) showed that sustained expression of BRAF carrying the V600E mutation (164757.0001) in human melanocytes induced cell cycle arrest, which was accompanied by the induction of both p16(INK4A) (600160) and senescence-associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital nevi were invariably positive for SA-beta-Gal expression, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, Michaloglou et al. (2005) observed a marked mosaic induction of p16(INK4a), suggesting that factors other than p16(INK4a) contribute to protection against BRAF(V600E)-driven proliferation. Nevi did not appear to suffer from telomere attrition, arguing in favor of an active oncogene-driven senescence process rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAF(V600E)-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiologic process. </p><p>Sommerer et al. (2005) analyzed the BRAF gene in 30 seminomas and 32 nonseminomatous GCTs (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma. The activating BRAF missense mutation 1796T-A (V600E; 164757.0001) was identified in 3 (9%) of 32 nonseminomatous tumors, within the embryonic carcinoma component; no BRAF mutations were found in the seminomas. </p><p>Curtin et al. (2005) demonstrated genetic diversity in melanomas related to susceptibility to ultraviolet light. They compared genomewide alternations in DNA copy number and mutation status of BRAF and NRAS (164790) in 126 melanomas from 4 clinical groups in which the degree of exposure to ultraviolet light differed: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from arms, soles, and subungual (acral) sites; and 20 mucosal melanomas. They found significant differences in the frequencies of regional changes in DNA copy number and the frequencies of mutations in BRAF among the 4 groups of melanomas. These samples could be correctly classified into the 4 groups with 70% accuracy on the basis of changes in the number of copies of genomic DNA. In 2-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84% accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89% accuracy. In 81% of melanomas on skin without chronic sun-induced damage, they found mutations in BRAF or NRAS; most melanomas in the other groups had mutations in neither gene. Melanomas with wildtype BRAF or NRAS frequently had increases in the number of copies of genes for cyclin-dependent kinase-4 (CDK4; 123829) and cyclin-1 (CCND1; 168461), which are downstream components of the RAS-BRAF pathway. In these studies, alterations in the number of copies of DNA was determined by comparative genomic hybridization. </p><p>Meltzer (2005) commented that information of the type provided by Curtin et al. (2005) will become increasingly important to the management of melanoma, and that a strong case can be made for monitoring BRAF mutation status in clinical trials of BRAF antagonists. Because BRAF mutations are uncommon in certain subgroups of patients, these groups may require uniquely tailored therapies. Clues from the gain of oncogenes identified by array-based comparative genomic hybridization may help identify new drug targets. </p><p>Aberrant DNA methylation of CpG islands has been extensively observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype,' or 'CIMP' (Toyota et al., 1999; Issa, 2004). However, the existence of CIMP has been challenged. To resolve this controversy, Weisenberger et al. (2006) conducted a systematic, stepwise screen of 195 CpG island methylation markers involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. They found that CIMP-positive tumors convincingly represented a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occurred almost exclusively as a consequence of CIMP-associated methylation of MLH1 (120436). </p><p>In a pilocytic astrocytoma (see 137800), Jones et al. (2009) identified a somatic 3-bp insertion at either nucleotide 1795 or 1796 within codon 598 of the BRAF gene. The mutation resulted in the introduction of an additional threonine near the mutational hotspot V600 and produced a constitutively active BRAF that induced anchorage-independent growth in mouse fibroblasts. </p><p>Yu et al. (2009) found that 42 (60%) of 70 sporadic pilocytic astrocytomas had rearrangements of the BRAF gene. Two additional tumors with no rearrangement carried a BRAF mutation. Twenty-two of 36 tumors with BRAF rearrangements had corresponding amplification of the neighboring HIPK2 gene (606868). However, 14 of 36 tumors with BRAF rearrangement had no detectable HIPK2 gene amplification. Six of 20 tumors demonstrated HIPK2 amplification without apparent BRAF rearrangement or mutation. Only 12 (17%) of the 70 tumors lacked detectable BRAF or HIPK2 alterations. Yu et al. (2009) concluded that BRAF rearrangement represents the most common genetic alteration in sporadic pilocytic astrocytomas. </p><p>Gala et al. (2014) analyzed tissue from sessile serrated adenomas (SSAs) from 19 individuals with sessile serrated polyposis cancer syndrome (SSPCS; 617108), and found that 18 of the genotyped SSAs carried the BRAF V600E mutation (164757.0001). </p><p>Yao et al. (2017) summarized 2 classes of oncogenic BRAF mutants that determine their sensitivity to inhibitors and described a third class. Class 1 BRAF mutations (V600 mutations) are RAS-independent, signal as monomers, and are sensitive to RAF monomer inhibitors. Class 2 BRAF mutants are RAS-independent, signal as constitutive dimers, and are resistant to vemurafenib but may be sensitive to RAF dimer inhibitors or MEK inhibitors. The third class of BRAF mutants comprises those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signaling is RAS-dependent. The mutants bind more tightly than wildtype BRAF to RAS-GTP, and their binding to and activation of wildtype CRAF (164760) is enhanced, leading to increased ERK signaling. The model suggests that dysregulation of signaling by these mutants in tumors requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbor RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signaling. These tumors are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. Yao et al. (2017) concluded that the 3 distinct functional classes of BRAF mutants in human tumors activate ERK signaling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway. </p><p>Nieto et al. (2017) showed that a kinase-inactive form of BRAF triggered lung adenocarcinoma in vivo in mice. </p><p><strong><em>Germline Mutations in Cardiofaciocutaneous Syndrome, Noonan Syndrome 7, and LEOPARD Syndrome 3</em></strong></p><p>
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Cardiofaciocutaneous (CFC) syndrome (see CFC1, 115150) is characterized by a distinctive facial appearance, heart defects, and mental retardation. Phenotypically, CFC overlaps Noonan syndrome (see 163950) and Costello syndrome (218040). The finding of HRAS (190020) mutations in individuals with Costello syndrome, and of PTPN11 (176876) mutations in individuals with Noonan syndrome, suggested to Niihori et al. (2006) that activation of the RAS-MAPK pathway is the common underlying mechanism of Noonan syndrome and Costello syndrome, and, hence, possibly of CFC syndrome. Niihori et al. (2006) sequenced the entire 18 coding exons of BRAF, an isoform in the RAF protooncogene family, in 40 individuals with CFC syndrome and identified 8 different mutations (e.g., 164757.0012) in 16 of the patients. They also found 2 mutations in the KRAS gene (190070.0009, 190070.0010). </p><p>Niihori et al. (2006) compared manifestations between KRAS-positive (CFC2; 615278) and BRAF-positive individuals with CFC and found similar frequencies of growth and mental retardation, craniofacial appearance, abnormal hair, and heart defects. However, there was a difference between the 2 groups in manifestations of skin abnormalities, including ichthyosis, hyperkeratosis, and hemangioma, which were observed in 13 BRAF-positive individuals but in no KRAS-positive individuals. Somatic mutations in BRAF were identified in 60% of malignant melanoma or nevi by Garnett and Marais (2004), suggesting that BRAF has an important role in the skin. </p><p>Rodriguez-Viciana et al. (2006) screened 23 CFC patients for mutations in BRAF. Eighteen of 23, or 78% of individuals, had mutations in BRAF; 11 distinct missense mutations clustered in 2 regions. Five individuals had a gln257-to-arg missense mutation (164757.0013) in the cysteine-rich domain of the conserved region 1 (CR1). The other cluster of mutations was in the protein kinase domain and involved exons 11, 12, 14, and 15. Five patients had heterogeneous missense mutations in exon 12. All parents and controls, totaling 40 phenotypically unaffected individuals, had none of these mutations, supporting the hypothesis that occurrence of CFC is sporadic. Rodriguez-Viciana et al. (2006) suggested that although the causative mutations in BRAF were heterogeneous, the distribution of mutations was specific and nonrandom. No frameshift, nonsense, or splice site mutations were detected in the cohort of patients; thus, BRAF haploinsufficiency is not a likely causative mechanism of CFC. Of the 5 individuals without BRAF mutation, 3 had mutation in either MEK1 (176872) or MEK2 (601263); the disease-causing mutation in the remaining 2 individuals was not identified. </p><p>In 2 patients originally diagnosed with Costello syndrome but with features overlapping those of CFC, in whom no HRAS mutations were found (Estep et al., 2006), Rauen (2006) identified missense mutations in the BRAF gene (164757.0020 and 164757.0021, respectively). The author noted that the mutations involved exons that were not previously described in CFC patients with BRAF mutations. Rauen (2006) stated that Costello syndrome and CFC can be distinguished by mutation analysis of genes in the RAS/MAPK pathway. </p><p>Schulz et al. (2008) identified 12 different mutations in the BRAF gene in 24 (47.0%) of 51 patients with cardiofaciocutaneous syndrome. </p><p>Sarkozy et al. (2009) identified heterozygous de novo mutations in the BRAF gene (see, e.g., 164757.0022, 164757.0023, 164757.0025, and 164757.0026) in 17 (52%) of 33 patients with CFC, 5 (1.9%) of 270 patients with Noonan syndrome (NS7; 613706), and 1 (17%) of 6 patients with LEOPARD syndrome (LPRD3; 613707). The mutations clustered in exon 6, encoding the cysteine-rich domain, and in exons 11 to 17, encoding the kinase domain, and did not overlap with cancer-causing BRAF mutations. In vitro functional expression studies of selected variants showed variable gain of function, but little or no transforming ability; all mutations had less activating potential than the common V600E mutation (164757.0001). However, the CFC-associated mutations tended to have a slightly more activating ability compared to the NS7-and LEOPARD-associated mutations. Sarkozy et al. (2009) noted that none of the NS7-associated mutations were found in patients with CFC, suggesting that the phenotypes resulting from germline BRAF mutations may be allele-specific. Overall, the findings expanded the phenotypic spectrum associated with germline BRAF mutations, suggesting a spectrum of diseases. </p>
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<strong>Cytogenetics</strong>
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<p>Jones et al. (2008) identified tandem duplications of about 2 Mb at chromosome 7q34 in 29 (66%) of 44 pilocytic astrocytomas (see 137800). These rearrangements were not observed in 244 higher grade astrocytomas. The duplications resulted in 3 different in-frame fusion genes containing most 5-prime exons of the KIAA1549 gene (613344) and several 3-prime exons of the BRAF gene. The most common fusion was between KIAA1549 exon 16 and BRAF exon 9, which occurred in 20 pilocytic astrocytomas. All breakpoint variants were expected to encode functionally similar proteins containing the C-terminal kinase domain of BRAF without the N-terminal BRAF autoregulatory domain. Similar to wildtype KIAA1549, which produces a short variant through the use of an internal promoter, PCR analysis detected both long and short variants of the KIAA1549/BRAF fusion transcript. COS-7 cells transfected with either long or short KIAA1549/BRAF fusion transcripts showed constitutive BRAF kinase activity, and NIH3T3 cells transfected with the short KIAA1549/BRAF fusion transcript showed anchorage-independent growth. </p>
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<p>Wojnowski et al. (1997) showed that mice with a targeted disruption in the Braf gene die of vascular defects during midgestation. Homozygous deficient embryos, unlike those homozygous for deficiency of Araf (311010) or Craf1, showed an increased number of endothelial precursor cells, dramatically enlarged blood vessels, and apoptotic death of differentiated endothelial cells. These results established Braf as a critical signaling factor in the formation of the vascular system and provided the first genetic evidence for an essential role of a Raf gene in the regulation of programmed cell death. </p><p>To build a model of human melanoma, Dankort et al. (2009) generated mice with conditional melanocyte-specific expression of Braf(V600E) (164757.0001). Upon induction of Braf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15 to 20 months. By contrast, expression of Braf(V600E) combined with Pten (601728) tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency, and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (see 601231) or MEK1/2 (176872, 601263) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with both drug inhibitors led to shrinkage of established melanomas. </p><p>Inoue et al. (2014) created heterozygous knockin mice expressing Braf with a gln241-to-arg (Q241R) mutation, which corresponds to the most frequent mutation in CFC syndrome, gln257 to arg (Q257R; 164757.0013). Braf Q241R/+ mice showed embryonic or neonatal lethality, with liver necrosis, edema, craniofacial abnormalities, and heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction, and ventricular septal defects. Braf Q241R/+ embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels. Prenatal treatment with a Mek inhibitor partly rescued embryonic lethality in Braf Q241R/+ embryos, with amelioration of craniofacial abnormalities and edema. One surviving pup was obtained following treatment with a histone-3 demethylase inhibitor. Combined treatment with Mek and histone-3 demethylase inhibitors further increased the survival rate in Braf Q241R/+ embryos and ameliorated enlarged cardiac valves. </p><p>Inoue et al. (2019) found that Braf Q241R/+ mice had decreased body weight, body length, and growth plate width compared with wildtype mice. Immunohistochemical analysis showed activated Erk in hypertrophic chondrocytes from Braf Q241R/+ mice, leading to impaired growth plate chondrogenesis without affecting chondrocyte proliferation and apoptosis, resulting in postnatal growth retardation. In addition, serum Igf1 (147440) and Igfbp3 (146732) levels in Braf Q241R/+ mice were transiently decreased due to poor nutritional status. Treatment with C-type natriuretic peptide (CNP; 600296), a stimulator of endochondral and long bone growth, increased body length and tail length in both Braf Q241R/+ and wildtype mice. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>27 Selected Examples):</strong>
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<strong>.0001 MELANOMA, MALIGNANT, SOMATIC</strong>
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COLORECTAL CANCER, SOMATIC, INCLUDED<br />
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THYROID CARCINOMA, PAPILLARY, SOMATIC, INCLUDED<br />
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NONSEMINOMATOUS GERM CELL TUMORS, SOMATIC, INCLUDED<br />
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ASTROCYTOMA, LOW-GRADE, SOMATIC, INCLUDED
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BRAF, VAL600GLU
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SNP: rs113488022,
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gnomAD: rs113488022,
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ClinVar: RCV000014992, RCV000014993, RCV000014994, RCV000022677, RCV000037936, RCV000067669, RCV000080903, RCV000208763, RCV000430562, RCV000443448, RCV000662278, RCV000860020, RCV001030023, RCV001248834, RCV001254874, RCV002051586, RCV003458334, RCV004018627, RCV004719648, RCV005089260
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<p>The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1. </p><p><strong><em>Malignant Melanoma</em></strong></p><p>
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Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway. </p><p>To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis. </p><p>Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition. </p><p>Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003). </p><p>Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response. </p><p>Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity. </p><p>Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. </p><p>Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies. </p><p>Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner. </p><p>Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations. </p><p>Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. </p><p>Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday. </p><p>Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers. </p><p><strong><em>Colorectal Carcinoma</em></strong></p><p>
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Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically. </p><p>Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E. </p><p>Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors. </p><p>Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients. </p><p>Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors. </p><p>Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108). </p><p><strong><em>Papillary Thyroid Carcinoma</em></strong></p><p>
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Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway. </p><p>Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation. </p><p>Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas. </p><p>Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas. </p><p>Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype. </p><p>Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings. </p><p>Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC. </p><p>In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas. </p><p>Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes. </p><p>In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue. </p><p>Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation. </p><p>Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC. </p><p>Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs. </p><p>Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth. </p><p>Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation. </p><p><strong><em>Nonseminomatous Germ Cell Tumors</em></strong></p><p>
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In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component. </p><p><strong><em>Astrocytoma</em></strong></p><p>
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Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors. </p><p><strong><em>Role in Neurodegeneration</em></strong></p><p>
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Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration. </p><p><strong><em>Variant Function</em></strong></p><p>
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Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation. </p><p>Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation. </p>
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</span>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 COLON CANCER, SOMATIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, ARG462ILE
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<br />
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SNP: rs180177032,
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ClinVar: RCV000014995
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 1 case of colorectal cancer (see 114500), Rajagopalan et al. (2002) observed a G-to-T transversion at nucleotide 1382 of the BRAF gene, resulting in an arg-ile substitution at codon 461 (R461I), in heterozygous state and as a somatic mutation. Based on the revised numbering system of Kumar et al. (2003), the ARG461ILE (1382G-T) mutation has been renumbered as ARG462ILE (1385G-T). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 COLORECTAL CANCER, SOMATIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, ILE463SER
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<br />
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SNP: rs180177033,
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ClinVar: RCV000014996
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a colorectal tumor (see 114500), Rajagopalan et al. (2002) identified a T-to-G transversion at nucleotide 1385 of the BRAF gene, resulting in an ile-ser substitution at codon 462 (I462S). This mutation was found in heterozygosity and was shown to be somatic. Based on the revised numbering system of Kumar et al. (2003), the ILE462SER (1385T-G) mutation has been renumbered as ILE463SER (1388T-G). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 COLORECTAL CANCER, SOMATIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, GLY464GLU
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<br />
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SNP: rs121913348,
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ClinVar: RCV000014997, RCV000033304, RCV000207512, RCV000844618, RCV001261044
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a colorectal tumor (see 114500), Rajagopalan et al. (2002) identified a G-to-A transition at nucleotide 1388 of the BRAF gene, resulting in a gly-glu substitution at codon 463 (G463E). This mutation was heterozygous and somatic. Based on the revised numbering system of Kumar et al. (2003), the GLY463GLU (1388G-A) mutation has been renumbered as GLY464GLU (1391G-A). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 COLORECTAL CANCER, SOMATIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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THYROID CARCINOMA, FOLLICULAR, SOMATIC, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, LYS601GLU
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<br />
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SNP: rs121913364,
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gnomAD: rs121913364,
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ClinVar: RCV000014999, RCV000015000, RCV000037938, RCV000433498
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Colorectal Cancer</em></strong></p><p>
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In a colorectal tumor (see 114500), Rajagopalan et al. (2002) identified an A-to-G transition at nucleotide 1798 of the BRAF gene, resulting in a lys-glu at codon 600 (K600E). This mutation was heterozygous and occurred somatically. Based on the revised numbering system of Kumar et al. (2003), the LYS600GLU (1798A-G) mutation has been renumbered as LYS601GLU (1801A-G). </p><p><strong><em>Thyroid Carcinoma, Follicular</em></strong></p><p>
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In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the K601E mutation in the BRAF gene in the cancerous thyroid tissue. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 ADENOCARCINOMA OF LUNG, SOMATIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, GLY466VAL
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<br />
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SNP: rs121913351,
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gnomAD: rs121913351,
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ClinVar: RCV000015001, RCV000037916
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Naoki et al. (2002) identified a gly465-to-val (G465V) mutation in exon 11 of the BRAF gene in 1 of 127 primary human lung adenocarcinomas (see 211980) screened. Based on the revised numbering system of Kumar et al. (2003), the GLY465VAL mutation has been renumbered as GLY466VAL. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 ADENOCARCINOMA OF LUNG, SOMATIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, LEU597ARG
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<br />
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SNP: rs121913366,
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ClinVar: RCV000015002
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Naoki et al. (2002) identified a leu596-to-arg (L596R) mutation in exon 15 of the BRAF gene in 1 of 127 primary human lung adenocarcinomas (see 211980) screened. Based on the revised numbering system of Kumar et al. (2003), the LEU596ARG mutation has been renumbered as LEU597ARG. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 NONSMALL CELL LUNG CANCER, SOMATIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, LEU597VAL
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<br />
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SNP: rs121913369,
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gnomAD: rs121913369,
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ClinVar: RCV000015003, RCV000030948, RCV000033333, RCV000208539, RCV000505705, RCV001813207, RCV002271369, RCV002513056
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a nonsmall cell lung carcinoma (see 211980), Brose et al. (2002) identified a leu596-to-val (L596V) change in exon 15 of the BRAF gene. Based on the revised numbering system of Kumar et al. (2003), the LEU596VAL mutation has been renumbered as LEU597VAL. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 LYMPHOMA, NON-HODGKIN, SOMATIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, GLY469ARG
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<br />
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SNP: rs121913357,
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ClinVar: RCV000015004, RCV000033306, RCV001778653
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>Lee et al. (2003) analyzed genomic DNA from 164 non-Hodgkin lymphomas (NHLs; see 605027) by PCR-based single-strand conformation polymorphism (SSCP) for detection of somatic mutations of BRAF (exons 11 and 15). BRAF mutations were detected in 4 NHLs (2.4%). Whereas most BRAF mutations in human cancers involve val600, e.g., 164757.0001, all of the 4 BRAF mutations in the NHLs involved other amino acids: 1 G468A (164757.0010), 2 G468R, and 1 D593G (164757.0011). Based on the revised numbering system of Kumar et al. (2003), the GLY468ARG mutation has been renumbered as GLY469ARG, the GLY468ALA mutation has been renumbered as GLY469ALA, and the ASP593GLY mutation has been renumbered as ASP594GLY. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0010 LYMPHOMA, NON-HODGKIN, SOMATIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, GLY469ALA
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<br />
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SNP: rs121913355,
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gnomAD: rs121913355,
|
|
|
|
|
|
ClinVar: RCV000015005, RCV000150210
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gly469-to-ala (G469A) mutation in the BRAF gene that was found in compound heterozygous state in genomic DNA from 164 non-Hodgkin lymphomas (see 605027) by Lee et al. (2003), see 164757.0009. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 LYMPHOMA, NON-HODGKIN, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, ASP594GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913338,
|
|
|
|
|
|
|
|
ClinVar: RCV000015006, RCV000037932, RCV000426107, RCV001238853
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the asp594-to-gly (D594G) mutation in the BRAF gene that was found in compound heterozygous state in genomic DNA from 164 non-Hodgkin lymphomas (see 605027) by Lee et al. (2003), see 164757.0009. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, ALA246PRO
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs180177034,
|
|
|
|
|
|
|
|
ClinVar: RCV000014998, RCV000033285, RCV000208416, RCV000235118, RCV000678900, RCV001047900, RCV003150930, RCV003338381
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 736G-C transversion in exon 6 of the BRAF gene, predicting an ala246-to-pro (A246P) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, GLN257ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs180177035,
|
|
|
|
|
|
|
|
ClinVar: RCV000015007, RCV000033289, RCV000080904, RCV000208766, RCV001027771, RCV001261967, RCV001329219, RCV001813208, RCV001813744, RCV003224098, RCV004018628, RCV004752707
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 unrelated patients with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 770A-G transition in exon 6 of the BRAF gene, predicting a gln257-to-arg (Q257R) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, GLY469GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913355,
|
|
|
|
|
|
gnomAD: rs121913355,
|
|
|
|
|
|
ClinVar: RCV000015008, RCV000033307, RCV000211748, RCV000212152, RCV000506575, RCV001813209, RCV002287336, RCV003450641
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 presumably unrelated individuals with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1406G-A transition in exon 11 of the BRAF gene, predicting a gly469-to-glu (G469E) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, LEU485PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs180177036,
|
|
|
|
|
|
|
|
ClinVar: RCV000015009, RCV000208764, RCV000211749, RCV000680805, RCV001172276, RCV001849264, RCV003415705, RCV004018629
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1455G-C transversion in exon 12 of the BRAF gene, predicting a leu485-to-phe (L485F) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, LYS499GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs180177037,
|
|
|
|
|
|
|
|
ClinVar: RCV000015010, RCV000207517, RCV000779848, RCV001813210, RCV004795412
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1495A-G transition in exon 12 of the BRAF gene, predicting a lys499-to-glu (K499E) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, GLU501LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs180177038,
|
|
|
|
|
|
|
|
ClinVar: RCV000015011, RCV000033315, RCV000207513, RCV000844616, RCV004018630
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cardiofaciocutaneous syndrome (CFC1; 115150), who was previously reported by Verloes et al. (1988), Niihori et al. (2006) found a heterozygous 1501G-A transition in exon 12 of the BRAF gene, predicting a glu501-to-lys (E501K) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, GLU501GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs180177039,
|
|
|
|
|
|
|
|
ClinVar: RCV000015012, RCV000207518, RCV000211750, RCV000414915, RCV000808147, RCV001273349
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 presumably unrelated patients with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1502A-G transition in exon 12 of the BRAF gene, predicting a glu501-to-gly (E501G) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, ASN581ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs180177040,
|
|
|
|
|
|
|
|
ClinVar: RCV000015013, RCV000033329, RCV000211751, RCV000474979, RCV003450642, RCV004018631
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 presumably unrelated patients with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1741A-G transition in exon 14 of the BRAF gene, predicting an asn581-to-asp (N581D) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, GLY534ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs180177041,
|
|
|
|
|
|
|
|
ClinVar: RCV000015014, RCV000208775, RCV000623633, RCV000779634, RCV001257953
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7-year-old boy with craniofacial features overlapping both cardiofaciocutaneous (CFC1; 115150) and Costello (218040) syndromes, in whom no HRAS (190020) mutation was found (Estep et al., 2006), Rauen (2006) identified a 1600G-C transversion in exon 13 of the BRAF gene, resulting in a gly534-to-arg (G534R) substitution, and noted that CFC-causing BRAF mutations had not previously been described in exon 13. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, ASP638GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs180177042,
|
|
|
|
|
|
|
|
ClinVar: RCV000015015, RCV000033337, RCV000622900, RCV000763164, RCV001851863
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 13-year-old girl with phenotypic features overlapping cardiofaciocutaneous (CFC1; 115150) and Costello (218040) syndromes, in whom no HRAS (190020) mutation was found (Estep et al., 2006), Rauen (2006) identified a 1914T-A transversion in exon 16 of the BRAF gene, resulting in an asp638-to-glu (D638E) substitution, and noted that CFC-causing BRAF mutations had not previously been described in exon 16. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 NOONAN SYNDROME 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, THR241MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906660,
|
|
|
|
|
|
gnomAD: rs387906660,
|
|
|
|
|
|
ClinVar: RCV000022678, RCV000033281, RCV000208540, RCV000211753, RCV000515432, RCV000545320, RCV001329218, RCV003230371, RCV003398558
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Noonan syndrome-7 (NS7; 613706), Sarkozy et al. (2009) identified a heterozygous de novo 722C-T transition in exon 6 of the BRAF gene, resulting in a thr241-to-met (T241M) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 NOONAN SYNDROME 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, THR241ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906660,
|
|
|
|
|
|
gnomAD: rs387906660,
|
|
|
|
|
|
ClinVar: RCV000022679, RCV000208548, RCV000624512, RCV001703420, RCV002513171
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Noonan syndrome-7 (NS7; 613706), Sarkozy et al. (2009) identified a heterozygous 722C-G transversion in exon 6 of the BRAF gene, resulting in a thr241-to-arg (T241R) substitution. The mutation was not identified in 150 controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 CARDIOFACIOCUTANEOUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LEOPARD SYNDROME 3, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRAF, THR241PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906661,
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|
ClinVar: RCV000022680, RCV000022681, RCV000055896, RCV000207516, RCV000211752, RCV000515363, RCV000654966, RCV001089761, RCV002288517
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
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<p />
|
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<p><strong><em>Cardiofaciocutaneous Syndrome 1</em></strong></p><p>
|
|
In 2 unrelated patients with cardiofaciocutaneous syndrome (CFC1; 115150), Schulz et al. (2008) identified a heterozygous 721A-C transversion in exon 6 of the BRAF gene, resulting in a thr241-to-pro (T241P) substitution in a conserved residue. </p><p><strong><em>LEOPARD Syndrome 3</em></strong></p><p>
|
|
Sarkozy et al. (2009) identified a heterozygous de novo T241P mutation in a patient with LEOPARD syndrome-3 (LPRD3; 613707). The patient had poor growth, craniofacial anomalies, short and webbed neck, mitral and aortic valve dysplasia, cognitive deficits, neonatal hypotonia, sensorineural deafness, and seizures. Other features included thorax defects, delayed puberty, reduced bone density, and fibrous cystic lesions of the pelvis. The skin showed hyperkeratosis, cafe-au-lait spots, multiple nevi, and dark colored lentigines that were spread on the whole body including the palms and soles. In vitro functional expression studies showed that the T241P mutant protein did not show transforming ability to cells in vitro, although there was a slight increase in MEK phosphorylation, suggesting activation of the downstream MAPK pathway. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0025 NOONAN SYNDROME 7</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, TRP531CYS
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<br />
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SNP: rs606231228,
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ClinVar: RCV000022682, RCV000191066, RCV000208560, RCV001781297
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated patients with Noonan syndrome-7 (NS7; 613706), Sarkozy et al. (2009) identified a heterozygous de novo 1593G-C transversion in exon 13 of the BRAF gene, resulting in a trp531-to-cys (W531C) substitution. In vitro functional expression studies showed that the W531C mutant protein did not show transforming ability to cells in vitro, although there was a slight increase in MEK phosphorylation, suggesting activation of the downstream MAPK pathway. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0026 NOONAN SYNDROME 7</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, LEU597VAL
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<br />
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|
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ClinVar: RCV000015003, RCV000030948, RCV000033333, RCV000208539, RCV000505705, RCV001813207, RCV002271369, RCV002513056
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In patient with Noonan syndrome-7 (NS7; 613706), Sarkozy et al. (2009) identified a heterozygous de novo 1789C-G transversion in exon 15 of the BRAF gene, resulting in a leu597-to-val (L597V) substitution. In vitro functional expression studies showed that the W531C mutant protein did not show transforming ability to cells in vitro, although there was a slight increase in MEK phosphorylation, suggesting activation of the downstream MAPK pathway. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0027 LEOPARD SYNDROME 3</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRAF, LEU245PHE
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<br />
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SNP: rs397507466,
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|
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gnomAD: rs397507466,
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|
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ClinVar: RCV000033283, RCV000037956, RCV000171142, RCV000469440, RCV000515291, RCV000788013
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</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a 17-year-old Czech boy with LEOPARD syndrome-3 (LPRD3; 613707), Koudova et al. (2009) identified a de novo heterozygous c.735A-G transition in exon 6 of the BRAF gene, resulting in a leu245-to-phe (L245F) substitution at a highly conserved residue. The mutation was not found in more than 300 controls, and functional studies were not performed. Notably, the patient did not have cognitive impairment. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Ball, D. W., Jin, N., Rosen, D. M., Dackiw, A., Sidransky, D., Xing, M., Nelkin, B. D.
|
|
<strong>Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244.</strong>
|
|
J. Clin. Endocr. Metab. 92: 4712-4718, 2007.
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[PubMed: 17878251]
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[Full Text: https://doi.org/10.1210/jc.2007-1184]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Bollag, G., Hirth, P., Tsai, J., Zhang, J., Ibrahim, P. N., Cho, H., Spevak, W., Zhang, C., Zhang, Y., Habets, G., Burton, E. A., Wong, B., and 28 others.
|
|
<strong>Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.</strong>
|
|
Nature 467: 596-599, 2010.
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[PubMed: 20823850]
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[Full Text: https://doi.org/10.1038/nature09454]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Boussemart, L., Malka-Mahieu, H., Girault, I., Allard, D., Hemmingsson, O., Tomasic, G., Thomas, M., Basmadjian, C., Ribeiro, N., Thuaud, F., Mateus, C., Routier, E., Kamsu-Kom, N., Agoussi, S., Eggermont, A. M., Desaubry, L., Robert, C., Vagner, S.
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|
<strong>eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.</strong>
|
|
Nature 513: 105-109, 2014.
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[PubMed: 25079330]
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[Full Text: https://doi.org/10.1038/nature13572]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Brady, D. C., Crowe, M. S., Turski, M. L., Hobbs, G. A., Yao, X., Chaikuad, A., Knapp, S., Xiao, K., Campbell, S. L., Thiele, D. J., Counter, C. M.
|
|
<strong>Copper is required for oncogenic BRAF signalling and tumorigenesis.</strong>
|
|
Nature 509: 492-496, 2014.
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[PubMed: 24717435]
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[Full Text: https://doi.org/10.1038/nature13180]
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</p>
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<li>
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<p class="mim-text-font">
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Brose, M. S., Volpe, P., Feldman, M., Kumar, M., Rishi, I., Gerrero, R., Einhorn, E., Herlyn, M., Minna, J., Nicholson, A., Roth, J. A., Albelda, S. M., Davies, H., Cox, C., Brignell, G., Stephens, P., Futreal, P. A., Wooster, R., Stratton, M. R., Weber, B. L.
|
|
<strong>BRAF and RAS mutations in human lung cancer and melanoma.</strong>
|
|
Cancer Res. 62: 6997-7000, 2002.
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[PubMed: 12460918]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chapman, P., Puzanov, I., sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R., Grippo, J., Nolop, K., Flaherty, K.
|
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<strong>Early efficacy signal demonstrated in advanced melanoma in a phase I trial of the oncogenic BRAF-selective inhibitor PLX4032. (Abstract)</strong>
|
|
Europ. J. Cancer Suppl. 7: 5 only, 2009.
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|
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ciampi, R., Knauf, J. A., Kerler, R., Gandhi, M., Zhu, Z., Nikiforova, M. N., Rabes, H. M., Fagin, J. A., Nikiforov, Y. E.
|
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<strong>Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer.</strong>
|
|
J. Clin. Invest. 115: 94-101, 2005.
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[PubMed: 15630448]
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[Full Text: https://doi.org/10.1172/JCI23237]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Curtin, J. A., Fridlyand, J., Kageshita, T., Patel, H. N., Busam, K. J., Kutzner, H., Cho, K.-H., Aiba, S., Brocker, E.-B., LeBoit, P. E., Pinkel, D., Bastian, B. C.
|
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<strong>Distinct sets of genetic alterations in melanoma.</strong>
|
|
New Eng. J. Med. 353: 2135-2147, 2005.
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[PubMed: 16291983]
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[Full Text: https://doi.org/10.1056/NEJMoa050092]
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|
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Dankort, D., Curley, D. P., Cartlidge, R. A., Nelson, B., Karnezis, A. N., Damsky, W. E., Jr., You, M. J., DePinho, R. A., McMahon, M., Bosenberg, M.
|
|
<strong>Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.</strong>
|
|
Nature Genet. 41: 544-552, 2009.
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|
|
[PubMed: 19282848]
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[Full Text: https://doi.org/10.1038/ng.356]
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., Davis, N., Dicks, E., and 40 others.
|
|
<strong>Mutations of the BRAF gene in human cancer.</strong>
|
|
Nature 417: 949-954, 2002.
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|
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|
|
[PubMed: 12068308]
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|
|
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|
|
[Full Text: https://doi.org/10.1038/nature00766]
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Davison, J. M., Rosenbaum, E., Barrett, T. L., Goldenberg, D., Hoque, M. O., Sidransky, D., Westra, W. H.
|
|
<strong>Absence of V599E BRAF mutations in desmoplastic melanomas.</strong>
|
|
Cancer 103: 788-792, 2005.
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|
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|
|
[PubMed: 15641040]
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|
|
[Full Text: https://doi.org/10.1002/cncr.20861]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Domingo, E., Laiho, P., Ollikainen, M., Pinto, M., Wang, L., French, A. J., Westra, J., Frebourg, T., Espin, E., Armengol, M., Hamelin, R., Yamamoto, H., Hofstra, R. M. W., Seruca, R., Lindblom, A., Peltomaki, P., Thibodeau, S. N., Aaltonen, L. A., Schwartz, S., Jr.
|
|
<strong>BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing.</strong>
|
|
J. Med. Genet. 41: 664-668, 2004.
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|
|
|
|
[PubMed: 15342696]
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[Full Text: https://doi.org/10.1136/jmg.2004.020651]
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|
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Durante, C., Puxeddu, E., Ferretti, E., Morisi, R., Moretti, S., Bruno, R., Barbi, F., Avenia, N., Scipioni, A., Verrienti, A., Tosi, E., Cavaliere, A., Gulino, A., Filetti, S., Russo, D.
|
|
<strong>BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism.</strong>
|
|
J. Clin. Endocr. Metab. 92: 2840-2843, 2007.
|
|
|
|
|
|
[PubMed: 17488796]
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|
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|
|
[Full Text: https://doi.org/10.1210/jc.2006-2707]
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|
|
|
|
</p>
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</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Edmunds, S. C., Cree, I. A., Di Nicolantonio, F., Hungerford, J. L., Hurren, J. S., Kelsell, D. P.
|
|
<strong>Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas.</strong>
|
|
Brit. J. Cancer 88: 1403-1405, 2003.
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|
|
|
|
|
[PubMed: 12778069]
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|
|
|
|
[Full Text: https://doi.org/10.1038/sj.bjc.6600919]
|
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|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Edwards, R. H., Ward, M. R., Wu, H., Medina, C. A., Brose, M. S., Volpe, P., Nussen-Lee, S., Haupt, H. M., Martin, A. M., Herlyn, M., Lessin, S. R., Weber, B. L.
|
|
<strong>Absence of BRAF mutations in UV-protected mucosal melanomas.</strong>
|
|
J. Med. Genet. 41: 270-272, 2004.
|
|
|
|
|
|
[PubMed: 15060100]
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|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.2003.016667]
|
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|
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., Rauen, K. A.
|
|
<strong>HRAS mutation in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.</strong>
|
|
Am. J. Med. Genet. 140A: 8-16, 2006.
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|
|
|
|
[PubMed: 16372351]
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|
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|
|
[Full Text: https://doi.org/10.1002/ajmg.a.31078]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Eychene, A., Barnier, J. V., Apiou, F., Dutrillaux, B., Calothy, G.
|
|
<strong>Chromosomal assignment of two human B-raf(Rmil) proto-oncogene loci: B-raf-1 encoding the p94(Braf/Rmil) and B-raf-2, a processed pseudogene.</strong>
|
|
Oncogene 7: 1657-1660, 1992.
|
|
|
|
|
|
[PubMed: 1630826]
|
|
|
|
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|
|
|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Flaherty, K., Puzanov, I., Sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R. J., Grippo, J. F., Nolop, K., Chapman, P.
|
|
<strong>Phase I study of PLX4032: proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. (Abstract-9000)</strong>
|
|
J. Clin. Oncol. 27 (suppl.): 15s, 2009.
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Flaherty, K. T., Puzanov, I., Kim, K. B., Ribas, A., McArthur, G. A., Sosman, J. A., O'Dwyer, P. J., Lee, R. J., Grippo, J. F., Nolop, K., Chapman, P. B.
|
|
<strong>Inhibition of mutated, activated BRAF in metastatic melanoma.</strong>
|
|
New Eng. J. Med. 363: 809-819, 2010.
|
|
|
|
|
|
[PubMed: 20818844]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJMoa1002011]
|
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|
|
</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Gala, M. K., Mizukami, Y., Le, L. P., Moriichi, K., Austin, T., Yamamoto, M., Lauwers, G. Y., Bardeesy, N., Chung, D. C.
|
|
<strong>Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.</strong>
|
|
Gastroenterology 146: 520-529, 2014.
|
|
|
|
|
|
[PubMed: 24512911]
|
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|
|
[Full Text: https://doi.org/10.1053/j.gastro.2013.10.045]
|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Garnett, M. J., Marais, R.
|
|
<strong>Guilty as charged: B-RAF is a human oncogene.</strong>
|
|
Cancer Cell 6: 313-319, 2004.
|
|
|
|
|
|
[PubMed: 15488754]
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|
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[Full Text: https://doi.org/10.1016/j.ccr.2004.09.022]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Giannini, R., Ugolini, C., Lupi, C., Proietti, A., Elisei, R., Salvatore, G., Berti, P., Materazzi, G., Miccoli, P., Santoro, M., Basolo, F.
|
|
<strong>The heterozygous distribution of BRAF mutation supports the independent clonal origin of distinct tumor foci in multifocal papillary thyroid carcinoma.</strong>
|
|
J. Clin. Endocr. Metab. 92: 3511-3516, 2007.
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Ada Hamosh - updated : 03/16/2020<br>Bao Lige - updated : 01/07/2020<br>Ada Hamosh - updated : 08/06/2018<br>Ada Hamosh - updated : 01/31/2018<br>Ada Hamosh - updated : 01/18/2018<br>Marla J. F. O'Neill - updated : 09/02/2016<br>Ada Hamosh - updated : 02/17/2016<br>Patricia A. Hartz - updated : 8/17/2015<br>Cassandra L. Kniffin - updated : 5/13/2015<br>Patricia A. Hartz - updated : 3/17/2015<br>Ada Hamosh - updated : 10/3/2014<br>Ada Hamosh - updated : 8/25/2014<br>Ada Hamosh - updated : 7/16/2014<br>Ada Hamosh - updated : 5/21/2014<br>Ada Hamosh - updated : 8/27/2013<br>Ada Hamosh - updated : 2/26/2013<br>Ada Hamosh - updated : 8/29/2012<br>Ada Hamosh - updated : 2/27/2012<br>Marla J. F. O'Neill - updated : 11/29/2011<br>Cassandra L. Kniffin - updated : 4/14/2011<br>Ada Hamosh - updated : 2/9/2011<br>Cassandra L. Kniffin - updated : 1/21/2011<br>Ada Hamosh - updated : 10/12/2010<br>Cassandra L. Kniffin - updated : 10/5/2010<br>Patricia A. Hartz - updated : 5/19/2010<br>Patricia A. Hartz - updated : 5/11/2010<br>Ada Hamosh - updated : 4/15/2010<br>Patricia A. Hartz - updated : 4/7/2010<br>Ada Hamosh - updated : 10/19/2009<br>Ada Hamosh - updated : 10/2/2009<br>Marla J. F. O'Neill - updated : 9/10/2009<br>Cassandra L. Kniffin - updated : 7/8/2009<br>Ada Hamosh - updated : 6/16/2009<br>John A. Phillips, III - updated : 3/9/2009<br>John A. Phillips, III - updated : 3/9/2009<br>John A. Phillips, III - updated : 1/14/2009<br>Jane Kelly - updated : 7/3/2008<br>John A. Phillips, III - updated : 5/28/2008<br>Cassandra L. Kniffin - updated : 5/15/2008<br>Cassandra L. Kniffin - updated : 3/17/2008<br>John A. Phillips, III - updated : 1/7/2008<br>John A. Phillips, III - updated : 4/10/2007<br>John A. Phillips, III - updated : 3/21/2007<br>Marla J. F. O'Neill - updated : 9/26/2006<br>Ada Hamosh - updated : 8/11/2006<br>Victor A. McKusick - updated : 6/30/2006<br>Ada Hamosh - updated : 6/8/2006<br>Ada Hamosh - updated : 4/19/2006<br>John A. Phillips, III - updated : 4/14/2006<br>John A. Phillips, III - updated : 4/4/2006<br>Victor A. McKusick - updated : 2/24/2006<br>Victor A. McKusick - updated : 12/1/2005<br>Marla J. F. O'Neill - updated : 10/11/2005<br>Ada Hamosh - updated : 9/7/2005<br>John A. Phillips, III - updated : 7/26/2005<br>John A. Phillips, III - updated : 7/11/2005<br>Victor A. McKusick - updated : 6/3/2005<br>John A. Phillips, III - updated : 4/26/2005<br>John A. Phillips, III - updated : 4/12/2005<br>John A. Phillips, III - updated : 3/31/2005<br>Marla J. F. O'Neill - updated : 2/2/2005<br>Victor A. McKusick - updated : 10/12/2004<br>Victor A. McKusick - updated : 4/29/2004<br>Victor A. McKusick - updated : 4/22/2004<br>Stylianos E. Antonarakis - updated : 4/13/2004<br>Victor A. McKusick - updated : 1/20/2004<br>Victor A. McKusick - updated : 9/2/2003<br>Victor A. McKusick - updated : 4/16/2003<br>Victor A. McKusick - updated : 3/3/2003<br>Ada Hamosh - updated : 9/17/2002<br>Ada Hamosh - updated : 7/10/2002<br>Ada Hamosh - updated : 11/3/1999<br>Victor A. McKusick - updated : 7/3/1997
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Victor A. McKusick : 12/1/1992
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