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Entry
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- *190070 - KRAS PROTOONCOGENE, GTPase; KRAS
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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">*190070</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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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="#description">Description</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="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</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="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#populationGenetics">Population Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/190070">Table View</a>
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</li>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</div>
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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=ENSG00000133703;t=ENST00000311936" 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=3845" 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=190070" 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="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=ENSG00000133703;t=ENST00000311936" 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_001369786,NM_001369787,NM_004985,NM_033360,XM_047428826" 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_004985" 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=190070" 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>
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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=01817&isoform_id=01817_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/KRAS" 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/131875,180592,180594,186764,190909,190910,553519,553520,553635,553637,1335026,1335027,4261653,9652341,15488883,15718761,15718763,20147727,30583145,119616917,119616918,119616919,119616920,145864620,145864654,145864662,145864666,151367901,151367903,158258457,166706781,291048722,291048873,300599559,311697329,380860911,440503003,576060859,1220516323,1220516325,1220516327,1621310587,1621312269,1682104285,1682104289,1682104291,1767238310,2098512370,2098512372,2098512374,2186152419,2186152421,2186152423,2186152425,2186152427,2186152429,2186152431,2186152433,2186152435,2186152437,2186152442,2186152446,2186152448,2186152450,2217288989,2462531871,2634041797" 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/P01116" 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>
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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=3845" 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=ENSG00000133703;t=ENST00000311936" 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=KRAS" 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=KRAS" 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+3845" 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/KRAS" 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:3845" 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/3845" 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=chr12&hgg_gene=ENST00000311936.8&hgg_start=25205246&hgg_end=25250929&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:6407" 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:6407" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=190070[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=190070[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/KRAS/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/ENSG00000133703" 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=KRAS" 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=KRAS" 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=KRAS" 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="http://www.LOVD.nl/KRAS" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=KRAS&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/PA30196" 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:6407" 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/FBgn0003205.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:96680" 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/KRAS#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:96680" 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/3845/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/OMIA001990/" 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=3845" 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=WBGene00002335;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-040808-67" 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:3845" 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=KRAS&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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</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>
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190070
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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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KRAS PROTOONCOGENE, GTPase; KRAS
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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-KI-RAS2 KIRSTEN RAT SARCOMA VIRAL ONCOGENE HOMOLOG<br />
|
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ONCOGENE KRAS2; KRAS2<br />
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KIRSTEN MURINE SARCOMA VIRUS 2; RASK2<br />
|
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C-KRAS
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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">
|
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V-KI-RAS1 PSEUDOGENE, INCLUDED; KRAS1P, INCLUDED
|
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</span>
|
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</div>
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<div>
|
|
<span class="h4 mim-font">
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|
ONCOGENE KRAS1, INCLUDED; KRAS1, INCLUDED<br />
|
|
KIRSTEN RAS1, INCLUDED; RASK1, INCLUDED
|
|
</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>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KRAS" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KRAS</a></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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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/12/240?start=-3&limit=10&highlight=240">12p12.1</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:25205246-25250929&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'})">12:25,205,246-25,250,929</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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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>
|
|
<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>
|
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Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=108010,109800,114480,615278,613659,601626,211980,609942,600268,260350,614470,163200" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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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="12">
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<span class="mim-font">
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<a href="/geneMap/12/240?start=-3&limit=10&highlight=240">
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12p12.1
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</a>
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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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Arteriovenous malformation of the brain, 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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<a href="/entry/108010"> 108010 </a>
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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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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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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">
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Bladder cancer, 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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<a href="/entry/109800"> 109800 </a>
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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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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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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">
|
|
Breast cancer, somatic
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|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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|
|
<a href="/entry/114480"> 114480 </a>
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
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|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
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</td>
|
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</tr>
|
|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiofaciocutaneous syndrome 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615278"> 615278 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
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</span>
|
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</td>
|
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</tr>
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|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Gastric cancer, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613659"> 613659 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukemia, acute myeloid, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/601626"> 601626 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Lung cancer, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/211980"> 211980 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Noonan syndrome 3
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/609942"> 609942 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Oculoectodermal syndrome, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/600268"> 600268 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Pancreatic carcinoma, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/260350"> 260350 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
RAS-associated autoimmune leukoproliferative disorder
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614470"> 614470 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/163200"> 163200 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
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|
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/190070" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/190070" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<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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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
|
<a id="text" class="mim-anchor"></a>
|
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<h4>
|
|
|
|
<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.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</span>
|
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</h4>
|
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<div>
|
|
<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
|
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<span class="mim-text-font">
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<p>The KRAS gene encodes the human cellular homolog of a transforming gene isolated from the Kirsten rat sarcoma virus. The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers. The most well-studied members of the RAS (derived from 'RAt Sarcoma' virus) gene family include KRAS, HRAS (<a href="/entry/190020">190020</a>), and NRAS (<a href="/entry/164790">164790</a>). These genes encode immunologically related proteins with a molecular mass of 21 kD and are homologs of rodent sarcoma virus genes that have transforming abilities. While these wildtype cellular proteins in humans play a vital role in normal tissue signaling, including proliferation, differentiation, and senescence, mutated genes are potent oncogenes that play a role in many human cancers (<a href="#101" class="mim-tip-reference" title="Weinberg, R. A. <strong>Fewer and fewer oncogenes.</strong> Cell 30: 3-4, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6751559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6751559</a>] [<a href="https://doi.org/10.1016/0092-8674(82)90003-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6751559">Weinberg, 1982</a>; <a href="#52" class="mim-tip-reference" title="Kranenburg, O. <strong>The KRAS oncogene: past, present, and future.</strong> Biochim. Biophys. Acta 1756: 81-82, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16269215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16269215</a>] [<a href="https://doi.org/10.1016/j.bbcan.2005.10.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16269215">Kranenburg, 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6751559+16269215" 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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</span>
|
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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="cloning" class="mim-anchor"></a>
|
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
|
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<p><a href="#28" class="mim-tip-reference" title="Der, C. J., Krontiris, T. G., Cooper, G. M. <strong>Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses.</strong> Proc. Nat. Acad. Sci. 79: 3637-3640, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6285355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6285355</a>] [<a href="https://doi.org/10.1073/pnas.79.11.3637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6285355">Der et al. (1982)</a> identified a new human DNA sequence homologous to the transforming oncogene of the Kirsten (ras-K) murine sarcoma virus within mouse 3T3 fibroblast cells transformed by DNA from an undifferentiated human lung cancer cell line (LX-1). The findings showed that KRAS could act as an oncogene in human cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6285355" 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="Chang, E. H., Gonda, M. A., Ellis, R. W., Scolnick, E. M., Lowy, D. R. <strong>Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses.</strong> Proc. Nat. Acad. Sci. 79: 4848-4852, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6289320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6289320</a>] [<a href="https://doi.org/10.1073/pnas.79.16.4848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6289320">Chang et al. (1982)</a> isolated clones corresponding to the human cellular KRAS gene from human placental and embryonic cDNA libraries. Two isoforms were identified, designated KRAS1 and KRAS2. KRAS1 contained 0.9 kb homologous to viral Kras and had 1 intervening sequence, and KRAS2 contained 0.3 kb homologous to viral Kras. <a href="#60" class="mim-tip-reference" title="McCoy, M. S., Toole, J. J., Cunningham, J. M., Chang, E. H., Lowy, D. R., Weinberg, R. A. <strong>Characterization of a human colon/lung carcinoma oncogene.</strong> Nature 302: 79-81, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6298638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6298638</a>] [<a href="https://doi.org/10.1038/302079a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6298638">McCoy et al. (1983)</a> characterized the KRAS gene isolated from a human colon adenocarcinoma cell line (SW840) and determined that it corresponded to KRAS2 as identified by <a href="#22" class="mim-tip-reference" title="Chang, E. H., Gonda, M. A., Ellis, R. W., Scolnick, E. M., Lowy, D. R. <strong>Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses.</strong> Proc. Nat. Acad. Sci. 79: 4848-4852, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6289320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6289320</a>] [<a href="https://doi.org/10.1073/pnas.79.16.4848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6289320">Chang et al. (1982)</a>. The KRAS2 oncogene was amplified in several tumor cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6289320+6298638" 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="#61" class="mim-tip-reference" title="McGrath, J. P., Capon, D. J., Smith, D. H., Chen, E. Y., Seeburg, P. H., Goeddel, D. V., Levinson, A. D. <strong>Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene.</strong> Nature 304: 501-506, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6308466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6308466</a>] [<a href="https://doi.org/10.1038/304501a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6308466">McGrath et al. (1983)</a> cloned the KRAS1 and KRAS2 genes and determined that the KRAS1 gene is a pseudogene. The KRAS2 gene encodes a 188-residue protein with a molecular mass of 21.66 kD. It showed only 6 amino acid differences from the viral gene. Comparison of the 2 KRAS genes showed that KRAS1 is lacking several intervening sequences, consistent with it being a pseudogene derived from a processed KRAS2 mRNA. The major KRAS2 mRNA transcript is 5.5 kb. Alternative splicing results in 2 variants, isoforms A and B, that differ in the C-terminal region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6308466" 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>Alternative splicing of exon 5 results in the KRASA and KRASB isoforms. Exon 6 contains the C-terminal region in KRASB, whereas it encodes the 3-prime untranslated region in KRASA. The differing C-terminal regions of these isoforms are subjected to posttranslational modifications. The differential posttranslational processing has profound functional effects leading to alternative trafficking pathways and protein localization (<a href="#19" class="mim-tip-reference" title="Carta, C., Pantaleoni, F., Bocchinfuso, G., Stella, L., Vasta, I., Sarkozy, A., Digilio, C., Palleschi, A., Pizzuti, A., Grammatico, P., Zampino, G., Dallapiccola, B., Gelb, B. D., Tartaglia, M. <strong>Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype.</strong> Am. J. Hum. Genet. 79: 129-135, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16773572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16773572</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16773572[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/10.1086/504394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16773572">Carta et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16773572" 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="#98" class="mim-tip-reference" title="Tsai, F. D., Lopes, M. S., Zhou, M., Court, H., Ponce, O., Fiordalisi, J. J., Gierut, J. J., Cox, A. D., Haigis, K. M., Philips, M. R. <strong>K-Ras4A splice variant is highly expressed in cancer and uses a hybrid membrane-targeting motif.</strong> Proc. Nat. Acad. Sci. 112: 779-784, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25561545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25561545</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25561545[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.1412811112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25561545">Tsai et al. (2015)</a> noted that the use of alternative fourth exons generates 2 KRAS variants, KRAS4A and KRAS4B, the produce isoforms with distinct membrane-targeting sequences. Using confocal microscopy, <a href="#98" class="mim-tip-reference" title="Tsai, F. D., Lopes, M. S., Zhou, M., Court, H., Ponce, O., Fiordalisi, J. J., Gierut, J. J., Cox, A. D., Haigis, K. M., Philips, M. R. <strong>K-Ras4A splice variant is highly expressed in cancer and uses a hybrid membrane-targeting motif.</strong> Proc. Nat. Acad. Sci. 112: 779-784, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25561545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25561545</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25561545[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.1412811112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25561545">Tsai et al. (2015)</a> showed that GFP-tagged KRAS4A localized exclusively to the plasma membrane (PM) of HEK293 cells. Palmitoylation of cys180 in the hypervariable region of KRAS4A was required for efficient targeting of KRAS4A to the PM, but a second signal could target KRAS4A to the PM in the absence of cys180 palmitoylation. The authors identified a C-terminal polybasic region in KRAS4A with 2 clusters of positively charged residues (PB1 and PB2). They found that both palmitoylation and PB2 were required for efficient targeting of KRAS4A to the PM. RT-PCR analysis showed that KRAS4A was expressed in all human cancer cell lines examined, especially in colorectal carcinoma and melanoma cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25561545" 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="#61" class="mim-tip-reference" title="McGrath, J. P., Capon, D. J., Smith, D. H., Chen, E. Y., Seeburg, P. H., Goeddel, D. V., Levinson, A. D. <strong>Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene.</strong> Nature 304: 501-506, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6308466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6308466</a>] [<a href="https://doi.org/10.1038/304501a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6308466">McGrath et al. (1983)</a> first reported that the KRAS2 gene spans 38 kb and contains 4 exons. Detailed sequence analysis showed that exon 4 has 2 forms, which the authors designated 4A and 4B. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6308466" 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 KRAS2 gene has been shown to have a total of 6 exons. Exons 2, 3, and 4 are invariant coding exons, whereas exon 5 undergoes alternative splicing. KRASB results from exon 5 skipping. In KRASA mRNA, exon 6 encodes the 3-prime untranslated region. In KRASB mRNA, exon 6 encodes the C-terminal region (<a href="#19" class="mim-tip-reference" title="Carta, C., Pantaleoni, F., Bocchinfuso, G., Stella, L., Vasta, I., Sarkozy, A., Digilio, C., Palleschi, A., Pizzuti, A., Grammatico, P., Zampino, G., Dallapiccola, B., Gelb, B. D., Tartaglia, M. <strong>Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype.</strong> Am. J. Hum. Genet. 79: 129-135, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16773572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16773572</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16773572[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/10.1086/504394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16773572">Carta et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16773572" 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>By in situ hybridization, <a href="#78" class="mim-tip-reference" title="Popescu, N. C., Amsbaugh, S. C., DiPaolo, J. A., Tronick, S. R., Aaronson, S. A., Swan, D. C. <strong>Chromosomal localization of three human ras genes by in situ molecular hybridization.</strong> Somat. Cell Molec. Genet. 11: 149-155, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3856955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3856955</a>] [<a href="https://doi.org/10.1007/BF01534703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3856955">Popescu et al. (1985)</a> mapped the KRAS2 gene to chromosome 12p12.1-p11.1. By linkage with RFLPs, <a href="#72" class="mim-tip-reference" title="O'Connell, P., Leppert, M., Hoff, M., Kumlin, E., Thomas, W., Cai, G., Law, M., White, R. <strong>A linkage map for human chromosome 12. (Abstract)</strong> Am. J. Hum. Genet. 37: A169 only, 1985."None>O'Connell et al. (1985)</a> confirmed the approximate location of KRAS2 on 12p12.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3856955" 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>Pseudogene</em></strong></p><p>
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The KRAS1 gene is a KRAS2 pseudogene and has been assigned to chromosome 6 (<a href="#71" class="mim-tip-reference" title="O'Brien, S. J., Nash, W. G., Goodwin, J. L., Lowry, D. R., Chang, E. H. <strong>Dispersion of the ras family of transforming genes to four different chromosomes in man.</strong> Nature 302: 839-842, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6843651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6843651</a>] [<a href="https://doi.org/10.1038/302839a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6843651">O'Brien et al., 1983</a>; <a href="#59" class="mim-tip-reference" title="McBride, O. W., Swan, D. C., Tronick, S. R., Gol, R., Klimanis, D., Moore, D. E., Aaronson, S. A. <strong>Regional chromosomal localization of N-ras, K-ras-1, K-ras-2 and myb oncogenes in human cells.</strong> Nucleic Acids Res. 11: 8221-8236, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6672765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6672765</a>] [<a href="https://doi.org/10.1093/nar/11.23.8221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6672765">McBride et al., 1983</a>). By in situ hybridization, <a href="#78" class="mim-tip-reference" title="Popescu, N. C., Amsbaugh, S. C., DiPaolo, J. A., Tronick, S. R., Aaronson, S. A., Swan, D. C. <strong>Chromosomal localization of three human ras genes by in situ molecular hybridization.</strong> Somat. Cell Molec. Genet. 11: 149-155, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3856955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3856955</a>] [<a href="https://doi.org/10.1007/BF01534703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3856955">Popescu et al. (1985)</a> assigned the KRAS1 gene to 6p12-p11. Because KRAS1 was found to be a pseudogene, its official symbol was changed to KRAS1P. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3856955+6843651+6672765" 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="#46" class="mim-tip-reference" title="Johnson, S. M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., Labourier, E., Reinert, K. L., Brown, D., Slack, F. J. <strong>RAS is regulated by the let-7 microRNA family.</strong> Cell 120: 635-647, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15766527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15766527</a>] [<a href="https://doi.org/10.1016/j.cell.2005.01.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15766527">Johnson et al. (2005)</a> found that the 3 human RAS genes, HRAS, KRAS, and NRAS, contain multiple let-7 (<a href="/entry/605386">605386</a>) complementary sites in their 3-prime UTRs that allow let-7 miRNA to regulate their expression. Let-7 expression was lower in lung tumors than in normal lung tissue, whereas expression of the RAS proteins was significantly higher in lung tumors, suggesting a possible mechanism for let-7 in cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15766527" 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="#11" class="mim-tip-reference" title="Bivona, T. G., Quatela, S. E., Bodemann, B. O., Ahearn, I. M., Soskis, M. J., Mor, A., Miura, J., Wiener, H. H., Wright, L., Saba, S. G., Yim, D., Fein, A., Perez de Castro, I., Li, C., Thompson, C. B., Cox, A. D., Philips, M. R. <strong>PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-X(L) on mitochondria and induces apoptosis.</strong> Molec. Cell 21: 481-493, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16483930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16483930</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.01.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16483930">Bivona et al. (2006)</a> found that the subcellular localization and function of Kras in mammalian cells was modulated by Pkc (see <a href="/entry/176960">176960</a>). Phosphorylation of Kras by Pkc agonists induced rapid translocation of Kras from the plasma membrane to several intracellular membranes, including the outer mitochondrial membrane, where Kras associated with Bclxl (BCL2L1; <a href="/entry/600039">600039</a>). Phosphorylated Kras required Bclxl for induction of apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16483930" 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="#105" class="mim-tip-reference" title="Yeung, T., Terebiznik, M., Yu, L., Silvius, J., Abidi, W. M., Philips, M., Levine, T., Kapus, A., Grinstein, S. <strong>Receptor activation alters inner surface potential during phagocytosis.</strong> Science 313: 347-351, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16857939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16857939</a>] [<a href="https://doi.org/10.1126/science.1129551" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16857939">Yeung et al. (2006)</a> devised genetically encoded probes to assess surface potential in intact cells. These probes revealed marked, localized alterations in the change of the inner surface of the plasma membrane of macrophages during the course of phagocytosis. Hydrolysis of phosphoinositides and displacement of phosphatidylserine accounted for the change in surface potential at the phagosomal cup. Signaling molecules such as KRAS, RAC1 (<a href="/entry/602048">602048</a>), and c-SRC (<a href="/entry/190090">190090</a>) that are targeted to the membrane by electrostatic interactions were rapidly released from membrane subdomains where the surface charge was altered by lipid remodeling during phagocytosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16857939" 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="#38" class="mim-tip-reference" title="Heo, W. D., Inoue, T., Park, W. S., Kim, M. L., Park, B. O., Wandless, T. J., Meyer, T. <strong>PI(3,4,5)P(3) and PI(4,5)P(2) lipids target proteins with polybasic clusters to the plasma membrane.</strong> Science 314: 1458-1461, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17095657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17095657</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17095657[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.1134389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17095657">Heo et al. (2006)</a> surveyed plasma membrane targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein-conjugated Ras, Rab, Arf, and Rho proteins. Of 48 proteins that were localized to the plasma membrane, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate lipids, <a href="#38" class="mim-tip-reference" title="Heo, W. D., Inoue, T., Park, W. S., Kim, M. L., Park, B. O., Wandless, T. J., Meyer, T. <strong>PI(3,4,5)P(3) and PI(4,5)P(2) lipids target proteins with polybasic clusters to the plasma membrane.</strong> Science 314: 1458-1461, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17095657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17095657</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17095657[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.1134389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17095657">Heo et al. (2006)</a> developed a chemical phosphatase activation method to deplete plasma membrane phosphatidylinositol 4,5-bisphosphate. Unexpectedly, proteins with polybasic clusters dissociated from the plasma membrane only when both phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate were depleted, arguing that both lipid second messengers jointly regulate plasma membrane targeting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17095657" 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="#32" class="mim-tip-reference" title="Gazin, C., Wajapeyee, N., Gobeil, S., Virbasius, C.-M., Green, M. R. <strong>An elaborate pathway required for Ras-mediated epigenetic silencing.</strong> Nature 449: 1073-1077, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17960246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17960246</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17960246[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/nature06251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17960246">Gazin et al. (2007)</a> performed a genomewide RNA interference (RNAi) screen in KRAS-transformed NIH 3T3 cells and identified 28 genes required for RAS-mediated epigenetic silencing of the proapoptotic FAS gene (TNFRSF6; <a href="/entry/134637">134637</a>). At least 9 of these RAS epigenetic silencing effectors (RESEs), including the DNA methyltransferase DNMT1 (<a href="/entry/126375">126375</a>), were directly associated with specific regions of the FAS promoter in KRAS-transformed NIH 3T3 cells but not in untransformed NIH 3T3 cells. RNAi-mediated knockdown of any of the 28 RESEs resulted in failure to recruit DNMT1 to the FAS promoter, loss of FAS promoter hypermethylation, and derepression of FAS expression. Analysis of 5 other epigenetically repressed genes indicated that RAS directs the silencing of multiple unrelated genes through a largely common pathway. Finally, <a href="#32" class="mim-tip-reference" title="Gazin, C., Wajapeyee, N., Gobeil, S., Virbasius, C.-M., Green, M. R. <strong>An elaborate pathway required for Ras-mediated epigenetic silencing.</strong> Nature 449: 1073-1077, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17960246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17960246</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17960246[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/nature06251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17960246">Gazin et al. (2007)</a> showed that 9 RESEs are required for anchorage-independent growth and tumorigenicity of KRAS-transformed NIH 3T3 cells; these 9 genes had not previously been implicated in transformation by RAS. <a href="#32" class="mim-tip-reference" title="Gazin, C., Wajapeyee, N., Gobeil, S., Virbasius, C.-M., Green, M. R. <strong>An elaborate pathway required for Ras-mediated epigenetic silencing.</strong> Nature 449: 1073-1077, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17960246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17960246</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17960246[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/nature06251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17960246">Gazin et al. (2007)</a> concluded that RAS-mediated epigenetic silencing occurs through a specific, complex pathway involving components that are required for maintenance of a fully transformed phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17960246" 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="Haigis, K. M., Kendall, K. R., Wang, Y., Cheung, A., Haigis, M. C., Glickman, J. N., Niwa-Kawakita, M., Sweet-Cordero, A., Sebolt-Leopold, J., Shannon, K. M., Settleman, J., Giovannini, M., Jacks, T. <strong>Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon.</strong> Nature Genet. 40: 600-608, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18372904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18372904</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18372904[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.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18372904">Haigis et al. (2008)</a> used genetically engineered mice to determine whether and how the related oncogenes Kras and Nras (<a href="/entry/164790">164790</a>) regulate homeostasis and tumorigenesis in the colon. Expression of Kras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek (see <a href="/entry/176872">176872</a>)-dependent manner. Nras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc (<a href="/entry/611731">611731</a>)-mutant colonic tumor, activation of Kras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This Kras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant Kras were hypersensitive to inhibition of Raf (see <a href="/entry/164760">164760</a>) but not Mek. <a href="#36" class="mim-tip-reference" title="Haigis, K. M., Kendall, K. R., Wang, Y., Cheung, A., Haigis, M. C., Glickman, J. N., Niwa-Kawakita, M., Sweet-Cordero, A., Sebolt-Leopold, J., Shannon, K. M., Settleman, J., Giovannini, M., Jacks, T. <strong>Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon.</strong> Nature Genet. 40: 600-608, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18372904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18372904</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18372904[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.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18372904">Haigis et al. (2008)</a> concluded that their studies demonstrated clear phenotypic differences between mutant Kras and Nras, and suggested that the oncogenic phenotype of mutant Kras might be mediated by noncanonical signaling through Ras effector pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18372904" 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>By studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF (<a href="/entry/164757">164757</a>) genes, <a href="#107" class="mim-tip-reference" title="Yun, J., Rago, C., Cheong, I., Pagliarini, R., Angenendt, P., Rajagopalan, H., Schmidt, K., Willson, J. K. V., Markowitz, S., Zhou, S., Diaz, L. A., Jr., Velculescu, V. E., Lengauer, C., Kinzler, K. W., Vogelstein, B., Papadopoulos, N. <strong>Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.</strong> Science 325: 1555-1559, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19661383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19661383</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19661383[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.1174229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19661383">Yun et al. (2009)</a> found that GLUT1 (<a href="/entry/138140">138140</a>), encoding glucose transporter-1, was 1 of 3 genes consistently upregulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low-glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wildtype KRAS alleles were subjected to a low-glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1, and 4% of these survivors had acquired KRAS mutations not present in their parents. The glycolysis inhibitor 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. <a href="#107" class="mim-tip-reference" title="Yun, J., Rago, C., Cheong, I., Pagliarini, R., Angenendt, P., Rajagopalan, H., Schmidt, K., Willson, J. K. V., Markowitz, S., Zhou, S., Diaz, L. A., Jr., Velculescu, V. E., Lengauer, C., Kinzler, K. W., Vogelstein, B., Papadopoulos, N. <strong>Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.</strong> Science 325: 1555-1559, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19661383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19661383</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19661383[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.1174229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19661383">Yun et al. (2009)</a> concluded that, taken together, these data suggested that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19661383" 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="#62" class="mim-tip-reference" title="Meylan, E., Dooley, A. L., Feldser, D. M., Shen, L., Turk, E., Ouyang, C., Jacks, T. <strong>Requirement for NF-kappa-B signalling in a mouse model of lung adenocarcinoma.</strong> Nature 462: 104-107, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19847165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19847165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19847165[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/nature08462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19847165">Meylan et al. (2009)</a> showed that the NF-kappa-B (see <a href="/entry/164011">164011</a>) pathway is required for the development of tumors in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (<a href="/entry/191170">191170</a>) and expression of oncogenic Kras containing the G12D mutation resulted in NF-kappa-B activation in primary mouse embryonic fibroblasts. Conversely, in lung tumor cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappa-B inhibition. Furthermore, the inhibition of NF-kappa-B signaling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumors in vivo, from the time of tumor initiation or after tumor progression, resulted in significantly reduced tumor development. <a href="#62" class="mim-tip-reference" title="Meylan, E., Dooley, A. L., Feldser, D. M., Shen, L., Turk, E., Ouyang, C., Jacks, T. <strong>Requirement for NF-kappa-B signalling in a mouse model of lung adenocarcinoma.</strong> Nature 462: 104-107, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19847165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19847165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19847165[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/nature08462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19847165">Meylan et al. (2009)</a> concluded that, together, their results indicated a critical function for NF-kappa-B signaling in lung tumor development and, further, that this requirement depends on p53 status. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19847165" 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="Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., Frohling, S., Chan, E. M., and 23 others. <strong>Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.</strong> Nature 462: 108-112, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19847166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19847166</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19847166[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/nature08460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19847166">Barbie et al. (2009)</a> used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the noncanonical I-kappa-B kinase TBK1 (<a href="/entry/604834">604834</a>) was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappa-B antiapoptotic signals involving c-REL (<a href="/entry/164910">164910</a>) and BCLXL (BCL2L1; <a href="/entry/600039">600039</a>) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. <a href="#7" class="mim-tip-reference" title="Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., Frohling, S., Chan, E. M., and 23 others. <strong>Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.</strong> Nature 462: 108-112, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19847166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19847166</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19847166[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/nature08460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19847166">Barbie et al. (2009)</a> concluded that TBK1 and NF-kappa-B signaling are essential in KRAS mutant tumors, and establish a general approach for the rational identification of codependent pathways in cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19847166" 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 Drosophila eye-antennal discs, cooperation between Ras(V12), an oncogenic form of the Ras85D protein, and loss-of-function mutations in the conserved tumor suppressor 'scribble' (<a href="/entry/607733">607733</a>) gives rise to metastatic tumors that display many characteristics observed in human cancers (summary by <a href="#102" class="mim-tip-reference" title="Wu, M., Pastor-Pareja, J. C., Xu, T. <strong>Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion.</strong> Nature 463: 545-548, 2010. Note: Erratum: Nature 543: 452 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20072127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20072127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20072127[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/nature08702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20072127">Wu et al., 2010</a>). <a href="#102" class="mim-tip-reference" title="Wu, M., Pastor-Pareja, J. C., Xu, T. <strong>Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion.</strong> Nature 463: 545-548, 2010. Note: Erratum: Nature 543: 452 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20072127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20072127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20072127[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/nature08702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20072127">Wu et al. (2010)</a> showed that clones of cells bearing different mutations can cooperate to promote tumor growth and invasion in Drosophila. The authors found that the Ras(V12) and scrib-null mutations can also cause tumors when they affect different adjacent epithelial cells. <a href="#102" class="mim-tip-reference" title="Wu, M., Pastor-Pareja, J. C., Xu, T. <strong>Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion.</strong> Nature 463: 545-548, 2010. Note: Erratum: Nature 543: 452 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20072127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20072127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20072127[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/nature08702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20072127">Wu et al. (2010)</a> showed that this interaction between Ras(V12) and scrib-null clones involves JNK signaling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines (see <a href="/entry/604260">604260</a>), a compensatory growth mechanism for tissue homeostasis. The development of Ras(V12) tumors can also be triggered by tissue damage, a stress condition that activates JNK signaling. The authors suggested that similar cooperative mechanisms could have a role in the development of human cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20072127" 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>Correct localization and signaling by farnesylated KRAS is regulated by the prenyl-binding protein PDE-delta (PDED; <a href="/entry/602676">602676</a>), which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm (<a href="#21" class="mim-tip-reference" title="Chandra, A., Grecco, H. E., Pisupati, V., Perera, D., Cassidy, L., Skoulidis, F., Ismail, S. A., Hedberg, C., Hanzal-Bayer, M., Venkitaraman, A. R., Wittinghofer, A., Bastiaens, P. I. H. <strong>The GDI-like solubilizing factor PDE-delta sustains the spatial organization and signalling of Ras family proteins.</strong> Nature Cell Biol. 14: 148-158, 2012. Note: Erratum: Nature Cell Biol. 14: 329 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22179043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22179043</a>] [<a href="https://doi.org/10.1038/ncb2394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22179043">Chandra et al., 2012</a>; <a href="#109" class="mim-tip-reference" title="Zhang, H., Liu, X., Zhang, K., Chen, C.-K., Frederick, J. M., Prestwich, G. D., Baehr, W. <strong>Photoreceptor cGMP phosphodiesterase delta subunit (PDE-delta) functions as a prenyl-binding protein.</strong> J. Biol. Chem. 279: 407-413, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14561760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14561760</a>] [<a href="https://doi.org/10.1074/jbc.M306559200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14561760">Zhang et al., 2004</a>). <a href="#111" class="mim-tip-reference" title="Zimmermann, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S. A., Triola, G., Wittinghofer, A., Bastiaens, P. I. H., Waldmann, H. <strong>Small molecule inhibition of the KRAS-PDE-delta interaction impairs oncogenic KRAS signalling.</strong> Nature 497: 638-642, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23698361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23698361</a>] [<a href="https://doi.org/10.1038/nature12205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23698361">Zimmermann et al. (2013)</a> reported that interfering with the binding of mammalian PDED to KRAS by means of small molecules provided a novel opportunity to suppress oncogenic RAS signaling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDED interaction that selectively bound to the prenyl-binding pocket of PDED with nanomolar affinity, inhibited oncogenic RAS signaling, and suppressed in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14561760+22179043+23698361" 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="#106" 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 or BRAF (<a href="/entry/164757">164757</a>) 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="#106" 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>Using coexpression analysis, <a href="#98" class="mim-tip-reference" title="Tsai, F. D., Lopes, M. S., Zhou, M., Court, H., Ponce, O., Fiordalisi, J. J., Gierut, J. J., Cox, A. D., Haigis, K. M., Philips, M. R. <strong>K-Ras4A splice variant is highly expressed in cancer and uses a hybrid membrane-targeting motif.</strong> Proc. Nat. Acad. Sci. 112: 779-784, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25561545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25561545</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25561545[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.1412811112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25561545">Tsai et al. (2015)</a> showed that, unlike KRAS4B, KRAS4A did not bind PDE6-delta, even though KRAS4A and KRAS4B had identical steady-state localizations at the PM. Further analysis revealed that both membrane-targeting signals of KRAS4A supported its downstream signaling, and that either of the 2 was sufficient for signal output. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25561545" 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="#104" class="mim-tip-reference" title="Yao, W., Rose, J. L., Wang, W., Seth, S., Jiang, H., Taguchi, A., Liu, J., Yan, L., Kapoor, A., Hou, P., Chen, Z., Wang, Q., and 26 others. <strong>Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer.</strong> Nature 568: 410-414, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30918400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30918400</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30918400[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/s41586-019-1062-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30918400">Yao et al. (2019)</a> developed an unbiased functional target discovery platform to query oncogeneic KRAS-dependent changes of the pancreatic ductal adenocarcinoma surfaceome, which revealed syndecan-1 (SDC1; <a href="/entry/186355">186355</a>) as a protein that is upregulated at the cell surface by oncogenic KRAS. Localization of SDC1 at the cell surface, where it regulates macropinocytosis, an essential metabolic pathway that fuels pancreatic ductal adenocarcinoma cell growth, is essential for disease maintenance and progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30918400" 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="Amendola, C. R., Mahaffey, J. P., Parker, S. J., Ahearn, I. M., Chen, W.-C., Zhou, M., Court, H., Shi, J., Mendoza, S. L., Morten, M. J., Rothenberg, E., Gottlieb, E., Wadghiri, Y. Z., Possemato, R., Hubbard, S. R., Balmain, A., Kimmelman, A. C., Philips, M. R. <strong>KRAS4A directly regulates hexokinase 1.</strong> Nature 576: 482-486, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31827279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31827279</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31827279[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/s41586-019-1832-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31827279">Amendola et al. (2019)</a> reported a direct, GTP-dependent interaction between the KRAS exon 4A-specific isoform KRAS4A and hexokinase-1 (HK1; <a href="/entry/142600">142600</a>) that alters the activity of the kinase, and thereby established that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31827279" 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>Regulation of KRAS Expression by KRAS1P Transcript Levels</em></strong></p><p>
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Following their finding that PTENP1 (<a href="/entry/613531">613531</a>), a pseudogene of the PTEN (<a href="/entry/601728">601728</a>) tumor suppressor gene, can derepress PTEN by acting as a decoy for PTEN-targeting miRNAS, <a href="#77" class="mim-tip-reference" title="Poliseno, L., Salmena, L., Zhang, J., Carver, B., Haveman, W. J., Pandolfi, P. P. <strong>A coding-independent function of gene and pseudogene mRNAs regulates tumour biology.</strong> Nature 465: 1033-1038, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577206</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20577206[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/nature09144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577206">Poliseno et al. (2010)</a> extended their analysis to the oncogene KRAS and its pseudogene KRAS1. KRAS1P 3-prime UTR overexpression in DU145 prostate cancer cells resulted in increased KRAS mRNA abundance and accelerated cell growth. They also found that KRAS and KRAS1P transcript levels were positively correlated in prostate cancer. Notably, the KRAS1P locus 6p12-p11 is amplified in different human tumors, including neuroblastoma, retinoblastoma, and hepatocellular carcinoma. <a href="#77" class="mim-tip-reference" title="Poliseno, L., Salmena, L., Zhang, J., Carver, B., Haveman, W. J., Pandolfi, P. P. <strong>A coding-independent function of gene and pseudogene mRNAs regulates tumour biology.</strong> Nature 465: 1033-1038, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577206</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20577206[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/nature09144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577206">Poliseno et al. (2010)</a> concluded that their findings together pointed to a putative protooncogenic role for KRAS1P, and supported the notion that pseudogene functions mirror the functions of their cognate genes as explained by a miRNA decoy mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577206" 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><strong><em>Role in Solid Tumors</em></strong></p><p>
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KRAS is said to be one of the most activated oncogenes, with 17 to 25% of all human tumors harboring an activating KRAS mutation (<a href="#52" class="mim-tip-reference" title="Kranenburg, O. <strong>The KRAS oncogene: past, present, and future.</strong> Biochim. Biophys. Acta 1756: 81-82, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16269215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16269215</a>] [<a href="https://doi.org/10.1016/j.bbcan.2005.10.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16269215">Kranenburg, 2005</a>). Critical regions of the KRAS gene for oncogenic activation include codons 12, 13, 59, 61, and 63 (<a href="#33" class="mim-tip-reference" title="Grimmond, S. M., Raghavan, D., Russell, P. J. <strong>Detection of a rare point mutation in Ki-ras of a human bladder cancer xenograft by polymerase chain reaction and direct sequencing.</strong> Urol. Res. 20: 121-126, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1553789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1553789</a>] [<a href="https://doi.org/10.1007/BF00296523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1553789">Grimmond et al., 1992</a>). These activating mutations cause Ras to accumulate in the active GTP-bound state by impairing intrinsic GTPase activity and conferring resistance to GTPase activating proteins (<a href="#108" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. <strong>Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.</strong> J. Med. Genet. 44: 131-135, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17056636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17056636</a>] [<a href="https://doi.org/10.1136/jmg.2006.046300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17056636">Zenker et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16269215+17056636+1553789" 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 study of 96 human tumors or tumor cell lines in the NIH 3T3 transforming system, <a href="#80" class="mim-tip-reference" title="Pulciani, S., Santos, E., Lauver, A. V., Long, L. K., Aaronson, S. A., Barbacid, M. <strong>Oncogene in solid human tumors.</strong> Nature 300: 539-542, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7144906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7144906</a>] [<a href="https://doi.org/10.1038/300539a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7144906">Pulciani et al. (1982)</a> found a mutated HRAS locus only in a single cancer cell line, whereas transforming KRAS genes were identified in 8 different carcinomas and sarcomas. KRAS appeared to be involved in malignancy much more often than HRAS. In a serous cystadenocarcinoma of the ovary (<a href="/entry/167000">167000</a>), <a href="#31" class="mim-tip-reference" title="Feig, L. A., Bast, R. C., Jr., Knapp, R. C., Cooper, G. M. <strong>Somatic activation of ras-K gene in a human ovarian carcinoma.</strong> Science 223: 698-701, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6695178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6695178</a>] [<a href="https://doi.org/10.1126/science.6695178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6695178">Feig et al. (1984)</a> showed the presence of an activated KRAS oncogene that was not activated in normal cells of the same patient. The transforming gene product displayed an electrophoretic mobility pattern that differed from that of KRAS transforming proteins in other tumors, suggesting a novel somatic KRAS mutation in this tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7144906+6695178" 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 cell line of human lung cancer (<a href="/entry/211980">211980</a>), <a href="#66" class="mim-tip-reference" title="Nakano, H., Yamamoto, F., Neville, C., Evans, D., Mizuno, T., Perucho, M. <strong>Isolation of transforming sequences of two human lung carcinomas: structural and functional analysis of the activated c-K-ras oncogenes.</strong> Proc. Nat. Acad. Sci. 81: 71-75, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6320174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6320174</a>] [<a href="https://doi.org/10.1073/pnas.81.1.71" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6320174">Nakano et al. (1984)</a> identified a mutation in the KRAS2 gene (<a href="#0001">190070.0001</a>), resulting in gene activation with transforming ability of the mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6320174" 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="#83" class="mim-tip-reference" title="Rodenhuis, S., van de Wetering, M. L., Mooi, W. J., Evers, S. G., van Zandwijk, N., Bos, J. L. <strong>Mutational activation of the K-RAS oncogene: a possible pathogenetic factor in adenocarcinoma of the lung.</strong> New Eng. J. Med. 317: 929-935, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3041218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3041218</a>] [<a href="https://doi.org/10.1056/NEJM198710083171504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3041218">Rodenhuis et al. (1987)</a> used a novel, highly sensitive assay based on oligonucleotide hybridization following in vitro amplification to examine DNA from 39 lung tumor specimens. The KRAS gene was found to be activated by point mutations in codon 12 in 5 of 10 adenocarcinomas. Two of these tumors were less than 2 cm in size and had not metastasized. No HRAS, KRAS, or NRAS mutations were observed in 15 squamous cell carcinomas, 10 large cell carcinomas, 1 carcinoid tumor, 2 metastatic adenocarcinomas from primary tumors outside the lung, and 1 small cell carcinoma. An approximately 20-fold amplification of the unmutated KRAS gene was observed in a tumor that proved to be a solitary lung metastasis of a rectal carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3041218" 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="#103" class="mim-tip-reference" title="Yanez, L., Groffen, J., Valenzuela, D. M. <strong>c-K-ras mutations in human carcinomas occur preferentially in codon 12.</strong> Oncogene 1: 315-318, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3330777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3330777</a>]" pmid="3330777">Yanez et al. (1987)</a> found mutations in codon 12 of the KRAS gene in 4 of 16 colon cancers (<a href="/entry/114500">114500</a>), 2 of 27 lung cancers, and 1 of 8 breast cancers (<a href="/entry/114480">114480</a>); no mutations were found at codon position 61. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3330777" 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 highest observed frequency of KRAS2 point mutations occurs in pancreatic carcinomas (<a href="/entry/260350">260350</a>), with 90% of the patients having at least 1 KRAS2 mutation (<a href="#2" class="mim-tip-reference" title="Almoguera, C., Shibata, D., Forrester, K., Martin, J., Arnheim, N., Perucho, M. <strong>Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.</strong> Cell 53: 549-554, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2453289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2453289</a>] [<a href="https://doi.org/10.1016/0092-8674(88)90571-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2453289">Almoguera et al., 1988</a>; <a href="#91" class="mim-tip-reference" title="Smit, V. T. H. B. M., Boot, A. J. M., Smits, A. M. M., Fleuren, G. J., Cornelisse, C. J., Bos, J. L. <strong>KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas.</strong> Nucleic Acids Res. 16: 7773-7782, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3047672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3047672</a>] [<a href="https://doi.org/10.1093/nar/16.16.7773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3047672">Smit et al., 1988</a>). Most of these mutations are in codon 12 (see, e.g., G12D, <a href="#0005">190070.0005</a> and G12V, <a href="#0006">190070.0006</a>) (<a href="#41" class="mim-tip-reference" title="Hruban, R. H., van Mansfeld, A. D. M., Offerhaus, G. J. A., van Weering, D. H. J., Allison, D. C., Goodman, S. N., Kensler, T. W., Bose, K. K., Cameron, J. L., Bos, J. L. <strong>K-ras oncogene activation in adenocarcinoma of the human pancreas: a study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization.</strong> Am. J. Path. 143: 545-554, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8342602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8342602</a>]" pmid="8342602">Hruban et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2453289+8342602+3047672" 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="#15" class="mim-tip-reference" title="Burmer, G. C., Loeb, L. A. <strong>Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma.</strong> Proc. Nat. Acad. Sci. 86: 2403-2407, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2648401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2648401</a>] [<a href="https://doi.org/10.1073/pnas.86.7.2403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2648401">Burmer and Loeb (1989)</a> identified KRAS2 mutations in both diploid and aneuploid cells in colon adenomas and carcinomas. Twenty-six of 40 colon carcinomas contained mutations at codon 12, and 9 of the 12 adenomas studied contained similar mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2648401" 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="#90" class="mim-tip-reference" title="Sidransky, D., Tokino, T., Hamilton, S. R., Kinzler, K. W., Levin, B., Frost, P., Vogelstein, B. <strong>Identification of RAS oncogene mutations in the stool of patients with curable colorectal tumors.</strong> Science 256: 102-105, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1566048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1566048</a>] [<a href="https://doi.org/10.1126/science.1566048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1566048">Sidransky et al. (1992)</a> found that KRAS mutations were detectable in DNA purified from stool in 8 of 9 patients with colorectal tumors that contained KRAS mutations. <a href="#95" class="mim-tip-reference" title="Takeda, S., Ichii, S., Nakamura, Y. <strong>Detection of K-ras mutation in sputum by mutant-allele-specific amplification (MASA).</strong> Hum. Mutat. 2: 112-117, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8318987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8318987</a>] [<a href="https://doi.org/10.1002/humu.1380020209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8318987">Takeda et al. (1993)</a> used a mutant-allele-specific amplification (MASA) method to detect KRAS mutations in cells obtained from the sputum of patients with lung cancer. A mutation was found in 1 of 5 patients studied. The authors suggested that the MASA system could be applied to an examination of metastatic lung carcinomas, particularly from adenocarcinomas of the colon and pancreas in which KRAS mutations are frequently detected, and to mass screening for colorectal tumors, using DNA isolated from feces as a template. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1566048+8318987" 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="Lee, K.-H., Lee, J.-S., Suh, C., Kim, S.-W., Kim, S.-B., Lee, J.-H., Lee, M.-S., Park, M.-Y., Sun, H.-S., Kim, S.-H. <strong>Clinicopathologic significance of the K-ras gene codon 12 point mutation in stomach cancer: an analysis of 140 cases.</strong> Cancer 75: 2794-2801, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7773929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7773929</a>] [<a href="https://doi.org/10.1002/1097-0142(19950615)75:12<2794::aid-cncr2820751203>3.0.co;2-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7773929">Lee et al. (1995)</a> identified mutations in codon 12 of the KRAS gene in 11 (7.9%) of 140 gastric cancers (<a href="/entry/613659">613659</a>). Seven cases had a G12S mutation (<a href="#0007">190070.0007</a>) and 2 had a G12D mutation (<a href="#0005">190070.0005</a>). Tumors located in the upper third of the stomach had a significantly higher frequency of KRAS codon 12 mutations (3 of 8; 37.5%) compared with tumors located in the middle (4 of 29; 13.8%) or lower (3 of 99; 3%) thirds of the stomach (P = 0.001). Among 8 patients with stomach cancer located in the upper part of the stomach, death occurred in 4 of 5 patients with tumors without KRAS gene mutations, but in none of the 3 patients with KRAS gene-mutated tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7773929" 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="Otori, K., Oda, Y., Sugiyama, K., Hasebe, T., Mukai, K., Fujii, T., Tajiri, H., Yoshida, S., Fukushima, S., Esumi, H. <strong>High frequency of K-ras mutations in human colorectal hyperplastic polyps.</strong> Gut 40: 660-663, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9203947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9203947</a>] [<a href="https://doi.org/10.1136/gut.40.5.660" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9203947">Otori et al. (1997)</a> examined tissue sections from 19 hyperplastic colorectal polyps for mutations in exons 12 and 13 of the KRAS gene. KRAS mutations were detected in 9 (47%) of 19 polyps, suggesting that some hyperplastic colorectal polyps may be true premalignant lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9203947" 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>KRAS activation has been recognized in microdissected foci of pancreatic intraepithelial neoplasia (<a href="#26" class="mim-tip-reference" title="Cubilla, A. L., Fitzgerald, P. J. <strong>Morphological lesions associated with human primary invasive nonendocrine pancreas cancer.</strong> Cancer Res. 36: 2690-2698, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1277176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1277176</a>]" pmid="1277176">Cubilla and Fitzgerald, 1976</a>; <a href="#40" class="mim-tip-reference" title="Hruban, R. H., Goggins, M., Parsons, J., Kern, S. E. <strong>Genetic progression in the pancreatic ducts. (Commentary)</strong> Clin. Cancer Res. 6: 2969-2972, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10955772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10955772</a>]" pmid="10955772">Hruban et al., 2000</a>; <a href="#42" class="mim-tip-reference" title="Hruban, R. H., Wilentz, R. E., Kern, S. E. <strong>Genetic progression in the pancreatic ducts.</strong> Am. J. Path. 156: 1821-1825, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854204</a>] [<a href="https://doi.org/10.1016/S0002-9440(10)65054-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854204">Hruban et al., 2000</a>), the candidate precursor lesion of pancreatic cancer previously known as ductal cell hyperplasia. <a href="#54" class="mim-tip-reference" title="Laghi, L., Orbetegli, O., Bianchi, P., Zerbi, A., Di Carlo, V., Boland, C. R., Malesci, A. <strong>Common occurrence of multiple K-RAS mutations in pancreatic cancers with associated precursor lesions and in biliary cancers.</strong> Oncogene 21: 4301-4306, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12082617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12082617</a>] [<a href="https://doi.org/10.1038/sj.onc.1205533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12082617">Laghi et al. (2002)</a> found that KRAS codon 12 was mutated in 34 of 41 (83%) pancreatic cancers and in 11 of 13 (85%) biliary cancers. Multiple distinct KRAS mutations were found in 16 pancreatic cancers and in 8 biliary cancers. Multiple KRAS mutations were more frequent in cancers with detectable pancreatic intraepithelial neoplasia than in those without, and individual precursor lesions of the same neoplastic pancreas harbored distinct mutations. The results indicated that clonally distinct precursor lesions of pancreatic cancer may variably contribute to tumor development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12082617+1277176+10854204+10955772" 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="Nikiforova, M. N., Lynch, R. A., Biddinger, P. W., Alexander, E. K., Dorn, G. W., II, Tallini, G., Kroll, T. G., Nikiforov, Y. E. <strong>RAS point mutations and PAX8-PPAR-gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma.</strong> J. Clin. Endocr. Metab. 88: 2318-2326, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12727991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12727991</a>] [<a href="https://doi.org/10.1210/jc.2002-021907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12727991">Nikiforova et al. (2003)</a> analyzed a series of 88 conventional follicular (<a href="/entry/188470">188470</a>) and Hurthle cell (<a href="/entry/607464">607464</a>) thyroid tumors for HRAS, NRAS, or KRAS mutations and PAX8 (<a href="/entry/167415">167415</a>)-PPARG (<a href="/entry/601487">601487</a>) rearrangements. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12727991" 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="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 mutations in the BRAF (<a href="/entry/164757">164757</a>) and KRAS genes in 330 colorectal tumors. There were 32 mutations in BRAF and 169 mutations in KRAS; no tumor exhibited mutations in both BRAF and KRAS. <a href="#81" 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 that BRAF and KRAS mutations are equivalent in their tumorigenic effects and are mutated at a similar phase of tumorigenesis, after initiation but before malignant conversion. <a href="#50" 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> 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/?term=14513361+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="#73" class="mim-tip-reference" title="Oliveira, C., Westra, J. L., Arango, D., Ollikainen, M., Domingo, E., Ferreira, A., Velho, S., Niessen, R., Lagerstedt, K., Alhopuro, P., Laiho, P., Veiga, I., and 16 others. <strong>Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status.</strong> Hum. Molec. Genet. 13: 2303-2311, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15294875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15294875</a>] [<a href="https://doi.org/10.1093/hmg/ddh238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15294875">Oliveira et al. (2004)</a> investigated KRAS in 158 hereditary nonpolyposis colorectal cancer (HNPCC2; <a href="/entry/609310">609310</a>) tumors from patients with germline MLH1 (<a href="/entry/120436">120436</a>), MSH2 (<a href="/entry/609309">609309</a>) or MSH6 (<a href="/entry/600678">600678</a>) mutations, 166 microsatellite-unstable (MSI-H), and 688 microsatellite-stable (MSS) sporadic carcinomas. All tumors were characterized for MSI and 81 of 166 sporadic MSI-H colorectal cancers were analyzed for MLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumors, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in MSH2, 32% (29/91) in MLH1, and 83% (5/6) in MSH6 (P = 0.01). KRAS mutation frequency was different between HNPCC, MSS, and MSI-H colorectal cancers (P = 0.002), and MSI-H with MLH1 hypermethylation (P = 0.005). Furthermore, HNPCC colorectal cancers had more G13D (<a href="#0003">190070.0003</a>) mutations than MSS (P less than 0.0001), MSI-H (P = 0.02) or MSI-H tumors with MLH1 hypermethylation (P = 0.03). HNPCC colorectal and sporadic MSI-H tumors without MLH1 hypermethylation shared similar KRAS mutation frequency, in particular G13D. The authors concluded that depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the MLH1 status) and MSS colorectal cancers may target distinct kinases within the RAS/RAF/MAPK pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15294875" 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="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 KRAS 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. KRAS mutations, all involving codon 12, were identified in 2 (7%) of 30 seminomas and 3 (9%) of 32 nonseminomas. <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="#34" class="mim-tip-reference" title="Groesser, L., Herschberger, E., Ruetten, A., Ruivenkamp, C., Lopriore, E., Zutt, M., Langmann, T., Singer, S., Klingseisen, L., Schneider-Brachert, W., Toll, A., Real, F. X., Landthaler, M., Hafner, C. <strong>Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.</strong> Nature Genet. 44: 783-787, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683711</a>] [<a href="https://doi.org/10.1038/ng.2316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683711">Groesser et al. (2012)</a> identified somatic mutations in the KRAS gene (G12D, <a href="#0005">190070.0005</a> and G12V, <a href="#0006">190070.0006</a>) in 3 (5%) of 65 nevus sebaceous tumors (see <a href="/entry/162900">162900</a>). The G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (<a href="/entry/163200">163200</a>). The authors postulated that the mosaic mutation likely extends to extracutaneous tissues in the latter disorder, which could explain the phenotypic pleiotropy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22683711" 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="#100" class="mim-tip-reference" title="Vermeulen, L., Morrissey, E., van der Heijden, M., Nicholson, A. M., Sottoriva, A., Buczacki, S., Kemp, R., Tavare, S., Winton, D. J. <strong>Defining stem cell dynamics in models of intestinal tumor initiation.</strong> Science 342: 995-998, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24264992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24264992</a>] [<a href="https://doi.org/10.1126/science.1243148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24264992">Vermeulen et al. (2013)</a> quantified the competitive advantage in tumor development of Apc (<a href="/entry/611731">611731</a>) loss, Kras activation, and p53 (<a href="/entry/191170">191170</a>) mutations in the mouse intestine. Their findings indicated that the fate conferred by these mutations is not deterministic, and many mutated stem cells are replaced by wildtype stem cells after biased but still stochastic events. Furthermore, <a href="#100" class="mim-tip-reference" title="Vermeulen, L., Morrissey, E., van der Heijden, M., Nicholson, A. M., Sottoriva, A., Buczacki, S., Kemp, R., Tavare, S., Winton, D. J. <strong>Defining stem cell dynamics in models of intestinal tumor initiation.</strong> Science 342: 995-998, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24264992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24264992</a>] [<a href="https://doi.org/10.1126/science.1243148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24264992">Vermeulen et al. (2013)</a> found that p53 mutations display a condition-dependent advantage, and especially in colitis-affected intestines, clones harboring mutations in this gene were favored. <a href="#100" class="mim-tip-reference" title="Vermeulen, L., Morrissey, E., van der Heijden, M., Nicholson, A. M., Sottoriva, A., Buczacki, S., Kemp, R., Tavare, S., Winton, D. J. <strong>Defining stem cell dynamics in models of intestinal tumor initiation.</strong> Science 342: 995-998, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24264992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24264992</a>] [<a href="https://doi.org/10.1126/science.1243148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24264992">Vermeulen et al. (2013)</a> concluded that their work confirmed the notion that the tissue architecture of the intestine suppresses the accumulation of mutated lineages. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24264992" 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>Hematologic Malignancies</em></strong></p><p>
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The myelodysplastic syndrome is a preleukemic hematologic disorder characterized by low blood counts, bone marrow cells of abnormal appearance, and progression to acute leukemia in as many as 30% of patients. <a href="#56" class="mim-tip-reference" title="Liu, E., Hjelle, B., Morgan, R., Hecht, F., Bishop, J. M. <strong>Mutations of the Kirsten-ras proto-oncogene in human preleukaemia.</strong> Nature 330: 186-188, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3313061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3313061</a>] [<a href="https://doi.org/10.1038/330186a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3313061">Liu et al. (1987)</a> identified a transforming allele in the KRAS gene in 2 of 4 patients with preleukemia and in 1 who progressed to acute leukemia from myelodysplastic syndrome. In 1 preleukemic patient, they detected a novel mutation in codon 13 of KRAS in bone marrow cells harvested 1.5 years before the acute leukemia developed. The findings provided evidence that RAS mutations may be involved in the early stages of human leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3313061" 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 the bone marrow of a 4-year-old child with acute myeloid leukemia (AML; <a href="/entry/601626">601626</a>), <a href="#12" class="mim-tip-reference" title="Bollag, G., Adler, F., elMasry, N., McCabe, P. C., Connor, E., Jr., Thompson, P., McCormick, F., Shannon, K. <strong>Biochemical characterization of a novel KRAS insertion mutation from a human leukemia.</strong> J. Biol. Chem. 271: 32491-32494, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8955068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8955068</a>] [<a href="https://doi.org/10.1074/jbc.271.51.32491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8955068">Bollag et al. (1996)</a> identified a somatic in-frame 3-bp insertion in the KRAS gene (<a href="#0008">190070.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8955068" 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="#10" class="mim-tip-reference" title="Bezieau, S., Devilder, M.-C., Avet-Loiseau, H., Mellerin, M.-P., Puthier, D., Pennarun, E., Rapp, M.-J., Harousseau, J.-L., Moisan, J.-P., Bataille, R. <strong>High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis.</strong> Hum. Mutat. 18: 212-224, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11524732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11524732</a>] [<a href="https://doi.org/10.1002/humu.1177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11524732">Bezieau et al. (2001)</a> used ARMS (allele-specific amplification method) to evaluate the incidence of NRAS- and KRAS2-activating mutations in patients with multiple myeloma (<a href="/entry/254500">254500</a>) and related disorders. Mutations were more frequent in KRAS2 than in NRAS. The authors concluded that early mutations in these 2 oncogenes may play a major role in the oncogenesis of multiple myeloma and primary plasma cell leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11524732" 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 white blood cells derived from 3 unrelated girls with juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>), <a href="#58" class="mim-tip-reference" title="Matsuda, K., Shimada, A., Yoshida, N., Ogawa, A., Watanabe, A., Yajima, S., Iizuka, S., Koike, K., Yanai, F., Kawasaki, K., Yanagimachi, M., Kikuchi, A., and 10 others. <strong>Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations.</strong> Blood 109: 5477-5480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332249</a>] [<a href="https://doi.org/10.1182/blood-2006-09-046649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17332249">Matsuda et al. (2007)</a> identified 3 different somatic heterozygous mutations in the KRAS gene (G13D, <a href="#0003">190070.0003</a>; G12D, <a href="#0005">190070.0005</a>; and G12S, <a href="#0007">190070.0007</a>). The patients were ascertained from a cohort of 80 children with JMML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17332249" 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 <a href="#16" class="mim-tip-reference" title="Cancer Genome Atlas Research Network. <strong>Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.</strong> New Eng. J. Med. 368: 2059-2074, 2013. Note: Erratum: New Eng. J. Med. 369: 98 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23634996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23634996</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23634996[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/NEJMoa1301689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23634996">Cancer Genome Atlas Research Network (2013)</a> analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. The <a href="#16" class="mim-tip-reference" title="Cancer Genome Atlas Research Network. <strong>Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.</strong> New Eng. J. Med. 368: 2059-2074, 2013. Note: Erratum: New Eng. J. Med. 369: 98 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23634996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23634996</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23634996[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/NEJMoa1301689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23634996">Cancer Genome Atlas Research Network (2013)</a> identified recurrent mutations in the NRAS (<a href="/entry/164790">164790</a>) or KRAS genes in 23/200 (12%) samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23634996" 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>RAS-Associated Autoimmune Leukoproliferative Disorder</em></strong></p><p>
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In 2 unrelated girls with RAS-associated autoimmune leukoproliferative disorder (RALD; <a href="/entry/614470">614470</a>), <a href="#67" class="mim-tip-reference" title="Niemela, J. E., Lu, L., Fleisher, T. A., Davis, J., Caminha, I., Natter, M., Beer, L. A., Dowdell, K. C., Pittaluga, S., Raffeld, M., Rao, V. K., Oliveira, J. B. <strong>Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.</strong> Blood 117: 2883-2886, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21079152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21079152</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21079152[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/10.1182/blood-2010-07-295501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21079152">Niemela et al. (2010)</a> identified different somatic heterozygous gain-of-function mutations in the KRAS gene (G12D, <a href="#0005">190070.0005</a> and G13C, <a href="#0023">190070.0023</a>). The patients presented in early childhood with lymphadenopathy, splenomegaly, and autoimmune disorders. One patient had recurrent infections. In vitro studies indicated that the activating KRAS mutations impaired cytokine withdrawal-induced T-cell apoptosis through suppression of the proapoptotic protein BIM (BCL2L11; <a href="/entry/603827">603827</a>) and facilitated lymphocyte proliferation through downregulation of CDKN1B (<a href="/entry/600778">600778</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21079152" 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>Cardiofaciocutaneous Syndrome, Noonan Syndrome 3, and Costello Syndrome</em></strong></p><p>
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Cardiofaciocutaneous (CFC) syndrome (see <a href="/entry/115150">115150</a>) is characterized by distinctive facial appearance, heart defects, and mental retardation. CFC shows phenotypic overlap with Noonan syndrome (see <a href="/entry/163950">163950</a>) and Costello syndrome (<a href="/entry/218040">218040</a>). Approximately 40% of individuals with clinically diagnosed Noonan syndrome have gain-of-function mutations in protein-tyrosine phosphatase SHP2 (PTPN11; <a href="/entry/176876">176876</a>). <a href="#5" class="mim-tip-reference" title="Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y. <strong>Germline mutations in HRAS proto-oncogene cause Costello syndrome.</strong> Nature Genet. 37: 1038-1040, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16170316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16170316</a>] [<a href="https://doi.org/10.1038/ng1641" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16170316">Aoki et al. (2005)</a> identified mutations in the HRAS gene in 12 of 13 individuals with Costello syndrome, suggesting that the activation of the RAS-MAPK pathway is the common underlying mechanism of Noonan syndrome, Costello syndrome, and possibly CFC syndrome. In 2 of 43 unrelated individuals with CFC syndrome (CFC2; <a href="/entry/615278">615278</a>), <a href="#68" 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> identified different heterozygous KRAS mutations (G60R, <a href="#0009">190070.0009</a> and D153V, <a href="#0010">190070.0010</a>). Neither mutation had previously been identified in individuals with cancer. In the same study, <a href="#68" 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 8 different mutations in the BRAF gene (<a href="/entry/164757">164757</a>), an isoform in the RAF protooncogene family, in 16 of 40 individuals with CFC syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16474404+16170316" 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="#86" class="mim-tip-reference" title="Schubbert, S., Zenker, M., Rowe, S. L., Boll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., Nguyen, H., West, B., Zhang, K. Y. J., Sistermans, E., Rauch, A., Niemeyer, C. M., Shannon, K., Kratz, C. P. <strong>Germline KRAS mutations cause Noonan syndrome.</strong> Nature Genet. 38: 331-336, 2006. Note: Erratum: Nature Genet. 38: 598 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474405</a>] [<a href="https://doi.org/10.1038/ng1748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474405">Schubbert et al. (2006)</a> identified 3 de novo germline KRAS mutations (<a href="#0010">190070.0010</a>-<a href="#0012">190070.0012</a>) in 5 individuals with Noonan syndrome-3 (NS3; <a href="/entry/609942">609942</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474405" 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 individuals exhibiting a severe Noonan syndrome-3 phenotype with features overlapping those of CFC and Costello syndromes, <a href="#19" class="mim-tip-reference" title="Carta, C., Pantaleoni, F., Bocchinfuso, G., Stella, L., Vasta, I., Sarkozy, A., Digilio, C., Palleschi, A., Pizzuti, A., Grammatico, P., Zampino, G., Dallapiccola, B., Gelb, B. D., Tartaglia, M. <strong>Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype.</strong> Am. J. Hum. Genet. 79: 129-135, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16773572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16773572</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16773572[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/10.1086/504394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16773572">Carta et al. (2006)</a> identified 2 different heterozygous KRAS mutations (<a href="#0014">190070.0014</a> and <a href="#0015">190070.0015</a>). Both mutations were de novo and affected exon 6, which encodes the C-terminal portion of KRAS isoform B but does not contribute to KRAS isoform A. Structural analysis indicated that both substitutions perturb the conformation of the guanine ring-binding pocket of the protein, predicting an increase in the guanine diphosphate/guanine triphosphate (GTP) dissociation rate that would favor GTP binding to the KRASB isoform and bypass the requirement for a guanine nucleotide exchange factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16773572" 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="#108" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. <strong>Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.</strong> J. Med. Genet. 44: 131-135, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17056636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17056636</a>] [<a href="https://doi.org/10.1136/jmg.2006.046300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17056636">Zenker et al. (2007)</a> identified 11 different germline mutations in the KRAS gene, including 8 novel mutations, in a total of 12 patients with a clinical diagnosis of CFC (2), Noonan syndrome-3 (7), CFC/Noonan syndrome overlap (1), or Costello syndrome (2). All patients showed mild to moderate mental retardation. The 2 unrelated infants with Costello syndrome had 2 different heterozygous mutations (<a href="#0017">190070.0017</a>-<a href="#0018">190070.0018</a>). Both patients had coarse facies, loose and redundant skin with deep palmar creases, heart defects, failure to thrive, and moderate mental retardation. <a href="#108" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. <strong>Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.</strong> J. Med. Genet. 44: 131-135, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17056636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17056636</a>] [<a href="https://doi.org/10.1136/jmg.2006.046300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17056636">Zenker et al. (2007)</a> noted that these patients may later develop features of CFC syndrome, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these diverse but phenotypically related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17056636" 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 20-year-old woman with clinical features typical of Costello syndrome and additional findings seen in Noonan syndrome, who was negative for mutations in the PTPN11 and HRAS genes, <a href="#8" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Brasil, A. S., Albano, L. M. J., Kim, C. A., Krieger, J. E. <strong>Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene.</strong> J. Hum. Genet. 52: 521-526, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17468812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17468812</a>] [<a href="https://doi.org/10.1007/s10038-007-0146-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17468812">Bertola et al. (2007)</a> identified a mutation in the KRAS gene (K5E; <a href="#0019">190070.0019</a>). The authors noted that this mutation was in the same codon as that of 1 of the patients reported by <a href="#108" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. <strong>Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.</strong> J. Med. Genet. 44: 131-135, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17056636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17056636</a>] [<a href="https://doi.org/10.1136/jmg.2006.046300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17056636">Zenker et al. (2007)</a> (K5N; <a href="#0017">190070.0017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17468812+17056636" 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="#87" 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 mutations in the KRAS gene in 3 (5.9%) of 51 CFC patients. <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>Development of Resistance to Chemotherapeutic Agents</em></strong></p><p>
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<a href="#63" class="mim-tip-reference" title="Misale, S., Yaeger, R., Hobor, S., Scala, E., Janakiraman, M., Liska, D., Valtorta, E., Schiavo, R., Buscarino, M., Siravegna, G., Bencardino, K., Cercek, A., and 14 others. <strong>Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.</strong> Nature 486: 532-536, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722830</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722830[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/nature11156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22722830">Misale et al. (2012)</a> showed that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR (<a href="/entry/131550">131550</a>) treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. <a href="#63" class="mim-tip-reference" title="Misale, S., Yaeger, R., Hobor, S., Scala, E., Janakiraman, M., Liska, D., Valtorta, E., Schiavo, R., Buscarino, M., Siravegna, G., Bencardino, K., Cercek, A., and 14 others. <strong>Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.</strong> Nature 486: 532-536, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722830</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722830[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/nature11156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22722830">Misale et al. (2012)</a> concluded that their results identified KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicated that the emergence of KRAS mutant clones can be detected noninvasively months before radiographic progression, and suggested early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22722830" 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="#29" class="mim-tip-reference" title="Diaz, L. A., Jr., Williams, R. T., Wu, J., Kinde, I., Hecht, J. R., Berlin, J., Allen, B., Bozic, I., Reiter, J. G., Nowak, M. A., Kinzler, K. W., Oliner, K. S., Vogelstein, B. <strong>The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers.</strong> Nature 486: 537-540, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722843</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722843[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/nature11219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22722843">Diaz et al. (2012)</a> determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. They found that 9 out of 24 (38%) patients whose tumors were initially KRAS wildtype developed detectable mutations in KRAS in their sera, 3 of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modeling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. <a href="#29" class="mim-tip-reference" title="Diaz, L. A., Jr., Williams, R. T., Wu, J., Kinde, I., Hecht, J. R., Berlin, J., Allen, B., Bozic, I., Reiter, J. G., Nowak, M. A., Kinzler, K. W., Oliner, K. S., Vogelstein, B. <strong>The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers.</strong> Nature 486: 537-540, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722843</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722843[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/nature11219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22722843">Diaz et al. (2012)</a> suggested that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a noninvasive manner. The results also explained why solid tumors develop resistance to targeted therapies in a highly reproducible fashion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22722843" 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>Arteriovenous Malformations of the Brain</em></strong></p><p>
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<a href="#70" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29298116[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/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al. (2018)</a> analyzed tissue and blood samples from patients with arteriovenous malformations of the brain (BAVM; <a href="/entry/108010">108010</a>) to detect somatic mutations. They performed exome DNA sequencing of BAVM tissue samples from 26 patients in the main study group and of paired blood samples from 17 of these patients, and then confirmed their findings using droplet digital PCR analysis of tissue samples from 39 patients in the initial study group (21 of whom had matching blood samples) and from 33 patients in an independent validation group. <a href="#70" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29298116[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/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al. (2018)</a> detected somatic activating KRAS mutations gly12 to asp (G12D; <a href="#0025">190070.0025</a>) and gly12 to val (G12V; <a href="#0026">190070.0026</a>) in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from BAVM, <a href="#70" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29298116[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/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al. (2018)</a> detected KRAS mutations and observed that expression of mutant KRAS (KRAS G12V) in endothelial cells in vitro induced increased ERK activity, increased expression of genes related to angiogenesis and Notch (<a href="/entry/190198">190198</a>) signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK-ERK signaling (see <a href="/entry/176872">176872</a>). <a href="#70" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29298116[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/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al. (2018)</a> concluded that they identified activating KRAS mutations in the majority of BAVM tissue samples that were analyzed, and proposed that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29298116" 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>Oculoectodermal Syndrome</em></strong></p><p>
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In affected tissue from 2 patients with oculoectodermal syndrome (OES; <a href="/entry/600268">600268</a>), <a href="#75" class="mim-tip-reference" title="Peacock, J. D., Dykema, K. J., Toriello, H. V., Mooney, M. R., Scholten, D. J., II, Winn, M. E., Borgman, A., Duesbery, N. S., Hiemenga, J. A., Liu, C., Campbell, S., Nickoloff, B. P., Williams, B. O., Steensma, M. <strong>Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations.</strong> Am. J. Med. Genet. 167A: 1429-1435, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25808193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25808193</a>] [<a href="https://doi.org/10.1002/ajmg.a.37048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25808193">Peacock et al. (2015)</a> identified somatic mosaicism for 2 different missense mutations in the KRAS gene, G12D (<a href="#0003">190070.0003</a>) and L19F (<a href="#0024">190070.0024</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25808193" 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 3 unrelated children with OES, <a href="#13" class="mim-tip-reference" title="Boppudi, S., Bogershausen, N., Hove, H. B., Percin, E. F., Aslan, D., Dvorsky, R., Kayhan, G., Li, Y., Cursiefen, C., Tantcheva-Poor, I., Toft, P. B., Bartsch, O., Lissewski, C., Wieland, I., Jakubiczka, S., Wollnik, B., Ahmadian, M. R., Heindl, L. M., Zenker, M. <strong>Specific mosaic KRAS mutations affecting codon 146 cause oculoectodermal syndrome and encephalocraniocutaneous lipomatosis.</strong> Clin. Genet. 90: 334-342, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26970110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26970110</a>] [<a href="https://doi.org/10.1111/cge.12775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26970110">Boppudi et al. (2016)</a> identified somatic missense mutations in the KRAS gene, A146T (<a href="#0027">190070.0027</a>) and A146V (<a href="#0028">190070.0028</a>), that were mosaic in lesional tissue and absent from leukocyte DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26970110" 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 4-year-old Mexican girl (patient 1) and an unrelated 12-year-old Mexican boy (patient 2) with OES, <a href="#20" class="mim-tip-reference" title="Chacon-Camacho, O. F., Lopez-Moreno, D., Morales-Sanchez, M. A., Hofmann, E., Pacheco-Quito, M., Wieland, I., Cortes-Gonzalez, V., Villanueva-Mendoza, C., Zenker, M., Zenteno, J. C. <strong>Expansion of the phenotypic spectrum and description of molecular findings in a cohort of patients with oculocutaneous mosaic RASopathies.</strong> Molec. Genet. Genomic Med. 7: e625, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30891959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30891959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30891959[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/mgg3.625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30891959">Chacon-Camacho et al. (2019)</a> identified somatic mosaicism for the previously reported KRAS variants, A146T and A146V, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30891959" 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>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between postzygotic somatic mutation in the KRAS gene and melorheostosis, see <a href="/entry/166700">166700</a>.</p>
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<p><a href="#4" class="mim-tip-reference" title="Andreyev, H. J. N., Tilsed, J. V. T., Cunningham, D., Sampson, S. A., Norman, A. R., Schneider, H. J., Clarke, P. A. <strong>K-ras mutations in patients with early colorectal cancers.</strong> Gut 41: 323-329, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9378386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9378386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9378386[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/10.1136/gut.41.3.323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9378386">Andreyev et al. (1997)</a> used PCR amplification and DNA sequencing to investigate KRAS exon 1 mutations (codons 12 and 13) in histologic sections of colorectal adenocarcinomas. They examined samples from 98 patients with Dukes stage A or B fully resected colorectal cancers. Fourteen of these patients had subsequently relapsed. The presence of a KRAS mutation was not associated with tumor stage or histologic grade; neither was there any association with those patients who relapsed. The authors concluded that detection of KRAS mutation in early colorectal adenocarcinomas was of no prognostic value. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9378386" 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="Porta, M., Malats, N., Jariod, M., Grimalt, J. O., Rifa, J., Carrato, A., Guarner, L., Salas, A., Santiago-Silva, M., Corominas, J. M., Andreu, M., Real, F. X. <strong>Serum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer.</strong> Lancet 354: 2125-2129, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10609819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10609819</a>] [<a href="https://doi.org/10.1016/s0140-6736(99)04232-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10609819">Porta et al. (1999)</a> found that serum concentrations of organochlorine compounds were significantly higher in patients with exocrine pancreatic cancer with a codon 12 KRAS2 mutation compared to cases without a mutation, with an odds ratio of 8.7 for one organochlorine and 5.3 for another organochlorine. These estimates held after adjusting for total lipids, other covariates, and total polychlorinated biphenyls (PCBs). A specific association was observed between the G12V (<a href="#0006">190070.0006</a>) mutation and both organochlorine concentrations, with an odds ratio of 15.9 and 24.1 for each of the compounds. A similar pattern was shown for the major diorthochlorinated PCBs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10609819" 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="#99" class="mim-tip-reference" title="Vasko, V., Ferrand, M., Di Cristofaro, J., Carayon, P., Henry, J. F., De Micco, C. <strong>Specific pattern of RAS oncogene mutations in follicular thyroid tumors.</strong> J. Clin. Endocr. Metab. 88: 2745-2752, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788883</a>] [<a href="https://doi.org/10.1210/jc.2002-021186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788883">Vasko et al. (2003)</a> performed a pooled analysis of 269 mutations in HRAS, KRAS, and NRAS garnered from 39 previous studies of thyroid tumors. Mutations in codon 61 of NRAS were significantly more frequent in follicular tumors (19%) than in papillary tumors (see <a href="/entry/188550">188550</a>) (5%) and significantly more frequent in malignant (25%) than in benign (14%) tumors. HRAS mutations in codons 12/13 were found in 2 to 3% of all types of tumors, but HRAS mutations in codon 61 were observed in only 1.4% of tumors, and almost all of them were malignant. KRAS mutations in exon 1 were found more often in papillary than follicular cancers (2.7% vs 1.6%) and were sometimes correlated with special epidemiologic circumstances. The second part of the study by <a href="#99" class="mim-tip-reference" title="Vasko, V., Ferrand, M., Di Cristofaro, J., Carayon, P., Henry, J. F., De Micco, C. <strong>Specific pattern of RAS oncogene mutations in follicular thyroid tumors.</strong> J. Clin. Endocr. Metab. 88: 2745-2752, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788883</a>] [<a href="https://doi.org/10.1210/jc.2002-021186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788883">Vasko et al. (2003)</a> involved analysis of 80 follicular tumors from patients living in Marseille (France) and Kiev (Ukraine). HRAS mutations in codons 12/13 were found in 12.5% of common adenomas and in 1 follicular carcinoma (2.9%). Mutations in codon 61 of NRAS occurred in 23.3% and 17.6% of atypical adenomas and follicular carcinomas, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788883" 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>Although several studies confirmed that approximately 40% of primary colorectal adenocarcinomas in humans contain a mutated form of the KRAS2 gene, the patterns of mutation at codons 12, 13, and 61 are not the same in different populations. <a href="#37" class="mim-tip-reference" title="Hayashi, N., Sugai, S., Ito, I., Nakamori, S., Ogawa, M., Nakamura, Y. <strong>Ethnic difference in the pattern of K-ras oncogene mutations in human colorectal cancers.</strong> Hum. Mutat. 8: 258-261, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8889585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8889585</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:3<258::AID-HUMU9>3.0.CO;2-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8889585">Hayashi et al. (1996)</a> used the MASA method to analyze the frequency and type of point mutations in these 3 codons in 319 colorectal cancer tissues collected from patients in Japan. They then compared these results with those from other sources to examine whether different geographic locations and environmental influences might impose distinct patterns on the spectrum of KRAS mutations. Comparing findings in the U.S., France, and Yugoslavia with those in Japan, a number of significant differences were found. A possible explanation put forth by <a href="#37" class="mim-tip-reference" title="Hayashi, N., Sugai, S., Ito, I., Nakamori, S., Ogawa, M., Nakamura, Y. <strong>Ethnic difference in the pattern of K-ras oncogene mutations in human colorectal cancers.</strong> Hum. Mutat. 8: 258-261, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8889585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8889585</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:3<258::AID-HUMU9>3.0.CO;2-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8889585">Hayashi et al. (1996)</a> was that an environmental carcinogen prevailing in a geographic region combines with the susceptibility of a particular tissue to dictate which type of DNA lesion will predominate. The predominance of G-to-A mutations among American and Japanese colorectal cancer patients could be attributable to alkylating agents or to the absence of direct interaction with any carcinogens. The prevalence of G-to-T mutations among Yugoslav and French patients might be ascribed to polycyclic aromatic hydrocarbons and heterocyclic amines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8889585" 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="#65" class="mim-tip-reference" title="Muller, R., Slamon, D. J., Adamson, E. D., Tremblay, J. M., Muller, D., Cline, M. J., Verma, I. M. <strong>Transcription of c-onc genes c-ras(Ki) and c-fms during mouse development.</strong> Molec. Cell. Biol. 3: 1062-1069, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6308423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6308423</a>] [<a href="https://doi.org/10.1128/mcb.3.6.1062-1069.1983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6308423">Muller et al. (1983)</a> found transcription of KRAS and the McDonough strain of feline sarcoma virus (FMS) gene (see <a href="/entry/164770">164770</a>) during mouse development. Furthermore, the differences in transcription in different tissues suggested a specific role for each: FMS was expressed in extraembryonic structures or in transport in these tissues, whereas KRAS was expressed ubiquitously. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6308423" 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="#39" class="mim-tip-reference" title="Holland, E. C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R. E., Fuller, G. N. <strong>Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice.</strong> Nature Genet. 25: 55-57, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802656</a>] [<a href="https://doi.org/10.1038/75596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802656">Holland et al. (2000)</a> transferred, in a tissue-specific manner, genes encoding activated forms of Ras and Akt (<a href="/entry/164730">164730</a>) to astrocytes and neural progenitors in mice. Although neither activated Ras nor Akt alone was sufficient to induce glioblastoma multiforme (GBM; <a href="/entry/137800">137800</a>) formation, the combination of activated Ras and Akt induced high-grade gliomas with the histologic features of human GBMs. These tumors appeared to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs, and <a href="#39" class="mim-tip-reference" title="Holland, E. C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R. E., Fuller, G. N. <strong>Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice.</strong> Nature Genet. 25: 55-57, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802656</a>] [<a href="https://doi.org/10.1038/75596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802656">Holland et al. (2000)</a> demonstrated that AKT activity is increased in most of these tumors, implying that combined activation of these 2 pathways accurately models the biology of this disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10802656" 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="Johnson, L., Mercer, K., Greenbaum, D., Bronson, R. T., Crowley, D., Tuveson, D. A., Jacks, T. <strong>Somatic activation of the K-ras oncogene causes early onset lung cancer in mice.</strong> Nature 410: 1111-1116, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11323676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11323676</a>] [<a href="https://doi.org/10.1038/35074129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11323676">Johnson et al. (2001)</a> used a variation of 'hit-and-run' gene targeting to create mouse strains carrying oncogenic alleles of Kras capable of activation only on a spontaneous recombination event in the whole animal. They demonstrated that mice carrying these mutations were highly predisposed to a range of tumor types, predominantly early-onset lung cancer. This model was further characterized by examining the effects of germline mutations in the p53 gene (<a href="/entry/191170">191170</a>), which is known to be mutated along with KRAS in human tumors. <a href="#45" class="mim-tip-reference" title="Johnson, L., Mercer, K., Greenbaum, D., Bronson, R. T., Crowley, D., Tuveson, D. A., Jacks, T. <strong>Somatic activation of the K-ras oncogene causes early onset lung cancer in mice.</strong> Nature 410: 1111-1116, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11323676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11323676</a>] [<a href="https://doi.org/10.1038/35074129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11323676">Johnson et al. (2001)</a> concluded that their approach had several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11323676" 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="#110" class="mim-tip-reference" title="Zhang, Z., Wang, Y., Vikis, H. G., Johnson, L., Liu, G., Li, J., Anderson, M. W., Sills, R. C., Hong, H. L., Devereux, T. R., Jacks, T., Guan, K.-L., You, M. <strong>Wildtype Kras2 can inhibit lung carcinogenesis in mice.</strong> Nature Genet. 29: 25-33, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528387</a>] [<a href="https://doi.org/10.1038/ng721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528387">Zhang et al. (2001)</a> presented evidence of a tumor suppressor role of wildtype KRAS2 in lung tumorigenesis. They found that heterozygous Kras2-deficient mice were highly susceptible to the chemical induction of lung tumors compared to wildtype mice. Activating Kras2 mutations were detected in all chemically induced lung tumors obtained from both wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhibited colony formation and tumor development by transformed NIH/3T3 cells. Allelic loss of wildtype Kras2 was found in 67 to 100% of chemically induced mouse lung adenocarcinomas that harbored a mutant Kras2 allele. These and other data strongly suggested that wildtype Kras2 has tumor suppressor activity and is frequently lost during lung tumor progression. <a href="#76" class="mim-tip-reference" title="Pfeifer, G. P. <strong>A new verdict for an old convict.</strong> Nature Genet. 29: 3-4, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528376</a>] [<a href="https://doi.org/10.1038/ng0901-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528376">Pfeifer (2001)</a> commented on these findings as representing 'a new verdict for an old convict.' He quoted evidence that the HRAS1 gene may also function as a tumor suppressor. <a href="#76" class="mim-tip-reference" title="Pfeifer, G. P. <strong>A new verdict for an old convict.</strong> Nature Genet. 29: 3-4, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528376</a>] [<a href="https://doi.org/10.1038/ng0901-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528376">Pfeifer (2001)</a> noted an interesting parallel to the p53 tumor suppressor, which was initially described as an oncogene, carrying point mutations in tumors. Later it was discovered that it is, in fact, the wildtype copy of the gene that functions as a tumor suppressor gene and is capable of reducing cell proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11528376+11528387" 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="Costa, R. M., Federov, N. B., Kogan, J. H., Murphy, G. G., Stern, J., Ohno, M., Kucherlapati, R., Jacks, T., Silva, A. J. <strong>Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.</strong> Nature 415: 526-530, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11793011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11793011</a>] [<a href="https://doi.org/10.1038/nature711" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11793011">Costa et al. (2002)</a> crossed Nf1 (<a href="/entry/613113">613113</a>) heterozygote mice with mice heterozygous for a null mutation in the Kras gene. Double heterozygotes with decreased Ras function had improved learning relative to Nf1 heterozygote mice. <a href="#25" class="mim-tip-reference" title="Costa, R. M., Federov, N. B., Kogan, J. H., Murphy, G. G., Stern, J., Ohno, M., Kucherlapati, R., Jacks, T., Silva, A. J. <strong>Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.</strong> Nature 415: 526-530, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11793011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11793011</a>] [<a href="https://doi.org/10.1038/nature711" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11793011">Costa et al. (2002)</a> also showed that the Nf1 +/- mice have increased GABA-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. <a href="#25" class="mim-tip-reference" title="Costa, R. M., Federov, N. B., Kogan, J. H., Murphy, G. G., Stern, J., Ohno, M., Kucherlapati, R., Jacks, T., Silva, A. J. <strong>Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.</strong> Nature 415: 526-530, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11793011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11793011</a>] [<a href="https://doi.org/10.1038/nature711" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11793011">Costa et al. (2002)</a> concluded that learning deficits associated with Nf1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11793011" 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>An S17N substitution in any of the RAS proteins produces dominant-inhibitory proteins with higher affinities for exchange factors than normal RAS. These mutants cannot interact with downstream effectors and therefore form unproductive complexes, preventing activation of endogenous RAS. Using experiments in COS-7 cells, mouse fibroblasts, and canine kidney cells, <a href="#57" class="mim-tip-reference" title="Matallanas, D., Arozarena, I., Berciano, M. T., Aaronson, D. S., Pellicer, A., Lafarga, M., Crespo, P. <strong>Differences on the inhibitory specificities of H-Ras, K-Ras, and N-Ras (N17) dominant negative mutants are related to their membrane microlocalization.</strong> J. Biol. Chem. 278: 4572-4581, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12458225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12458225</a>] [<a href="https://doi.org/10.1074/jbc.M209807200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12458225">Matallanas et al. (2003)</a> found that the Hras, Kras, and Nras S17N mutants exhibited distinct inhibitory effects that appeared to be due largely to their specific membrane localizations. The authors demonstrated that Hras is present in caveolae, lipid rafts, and bulk disordered membranes, whereas Kras and Nras are present primarily in disordered membranes and lipid rafts, respectively. Thus, the Hras S17N mutant inhibited activation of all 3 wildtype RAS isoforms, the Kras S17N mutant inhibited wildtype Kras and the portion of Hras in disordered membranes, and the Nras S17N mutant inhibited wildtype Nras and the portion of Hras in lipid rafts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12458225" 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>By delivering a recombinant adenoviral vector expressing Cre recombinase to the bursal cavity that encloses the ovary, <a href="#30" class="mim-tip-reference" title="Dinulescu, D. M., Ince, T. A., Quade, B. J., Shafer, S. A., Crowley, D., Jacks, T. <strong>Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer.</strong> Nature Med. 11: 63-70, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15619626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15619626</a>] [<a href="https://doi.org/10.1038/nm1173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15619626">Dinulescu et al. (2005)</a> expressed an oncogenic Kras allele within the ovarian surface epithelium and observed benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma (<a href="/entry/167000">167000</a>); 7 of 15 mice (47%) also developed peritoneal endometriosis (<a href="/entry/131200">131200</a>). When the Kras mutation was combined with conditional deletion of Pten (<a href="/entry/601728">601728</a>), all mice developed invasive endometrioid ovarian adenocarcinomas. <a href="#30" class="mim-tip-reference" title="Dinulescu, D. M., Ince, T. A., Quade, B. J., Shafer, S. A., Crowley, D., Jacks, T. <strong>Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer.</strong> Nature Med. 11: 63-70, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15619626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15619626</a>] [<a href="https://doi.org/10.1038/nm1173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15619626">Dinulescu et al. (2005)</a> stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15619626" 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="#24" class="mim-tip-reference" title="Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A. J., Barradas, M., Benguria, A., Zaballos, A., Flores, J. M., Barbacid, M., Beach, D., Serrano, M. <strong>Senescence in premalignant tumours. (Letter)</strong> Nature 436: 642 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16079833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16079833</a>] [<a href="https://doi.org/10.1038/436642a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16079833">Collado et al. (2005)</a> used a mouse model for cancer initiation in humans: the animals had a conditional oncogenic K-rasV12 (<a href="#0006">190070.0006</a>) allele that is activated only by the enzyme Cre recombinase, causing them to develop multiple lung adenomas (premalignant tumors) and a few lung adenocarcinomas (malignant tumors). Senescence markers previously identified in cultured cells were used to detect oncogene-induced senescence in lung sections from control mice (expressing Cre) and from K-rasV12-expressing mice (expressing Cre and activated K-rasV12). <a href="#24" class="mim-tip-reference" title="Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A. J., Barradas, M., Benguria, A., Zaballos, A., Flores, J. M., Barbacid, M., Beach, D., Serrano, M. <strong>Senescence in premalignant tumours. (Letter)</strong> Nature 436: 642 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16079833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16079833</a>] [<a href="https://doi.org/10.1038/436642a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16079833">Collado et al. (2005)</a> analyzed p16(INK4a) (<a href="/entry/600160">600160</a>), an effector of in vitro oncogene-induced senescence, and de novo markers that were identified by using DNA microarray analysis of in vitro oncogene-induced senescence. These de novo markers are p15(INK4b), also known as CDKN2B (<a href="/entry/600431">600431</a>), DEC1 (BHLHB2; <a href="/entry/604256">604256</a>), and DCR2 (TNFRSF10D; <a href="/entry/603614">603614</a>). Staining with antibodies against p16(INK4a), p15(INK4b), DEC1, and DCR2 revealed abundant positive cells in adenomas, whereas adenocarcinomas were essentially negative. By contrast, the proliferation marker Ki-67 revealed a weak proliferative index in adenomas compared with adenocarcinomas. <a href="#24" class="mim-tip-reference" title="Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A. J., Barradas, M., Benguria, A., Zaballos, A., Flores, J. M., Barbacid, M., Beach, D., Serrano, M. <strong>Senescence in premalignant tumours. (Letter)</strong> Nature 436: 642 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16079833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16079833</a>] [<a href="https://doi.org/10.1038/436642a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16079833">Collado et al. (2005)</a> concluded that oncogene-induced senescence may help to restrict tumor progression. They concluded that a substantial number of cells in premalignant tumors undergo oncogene-induced senescence, but that cells in malignant tumors are unable to do this owing to the loss of oncogene-induced senescence effectors such as p16(INK4a) or p53. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16079833" 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 an Hras (<a href="/entry/190020">190020</a>) knockin mouse model, <a href="#96" class="mim-tip-reference" title="To, M. D., Wong, C. E., Karnezis, A. N., Del Rosario, R., Di Lauro, R., Balmain, A. <strong>Kras regulatory elements and exon 4A determine mutation specificity in lung cancer.</strong> Nature Genet. 40: 1240-1244, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18758463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18758463</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18758463[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.211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18758463">To et al. (2008)</a> demonstrated that specificity for Kras mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target Ras genes. Although the Kras 4A isoform is dispensable for mouse development, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wildtype Kras on the mutant allele. Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The 2 Kras isoforms undergo different posttranslational modifications. <a href="#96" class="mim-tip-reference" title="To, M. D., Wong, C. E., Karnezis, A. N., Del Rosario, R., Di Lauro, R., Balmain, A. <strong>Kras regulatory elements and exon 4A determine mutation specificity in lung cancer.</strong> Nature Genet. 40: 1240-1244, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18758463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18758463</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18758463[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.211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18758463">To et al. (2008)</a> concluded that their findings may have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18758463" 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="Junttila, M. R., Karnezis, A. N., Garcia, D., Madriles, F., Kortlever, R. M., Rostker, F., Swigart, L. B., Pham, D. M., Seo, Y., Evan, G. I., Martins, C. P. <strong>Selective activation of p53-mediated tumour suppression in high-grade tumours.</strong> Nature 468: 567-571, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21107427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21107427</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21107427[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/nature09526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21107427">Junttila et al. (2010)</a> modeled the probable therapeutic impact of p53 (<a href="/entry/191170">191170</a>) restoration in a spontaneously evolving mouse model of nonsmall cell lung cancer (NSCLC) initiated by sporadic oncogenic activation of endogenous KRAS developed by <a href="#43" class="mim-tip-reference" title="Jackson, E. L., Willis, N., Mercer, K., Bronson, R. T., Crowley, D., Montoya, R., Jacks, T., Tuveson, D. A. <strong>Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.</strong> Genes Dev. 15: 3243-3248, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11751630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11751630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11751630[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/10.1101/gad.943001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11751630">Jackson et al. (2001)</a>. Surprisingly, p53 restoration failed to induce significant regression of established tumors, although it did result in a significant decrease in the relative proportion of high-grade tumors. This was due to selective activation of p53 only in the more aggressive tumor cells within each tumor. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signaling sensor p19(ARF) (<a href="/entry/600160">600160</a>). <a href="#47" class="mim-tip-reference" title="Junttila, M. R., Karnezis, A. N., Garcia, D., Madriles, F., Kortlever, R. M., Rostker, F., Swigart, L. B., Pham, D. M., Seo, Y., Evan, G. I., Martins, C. P. <strong>Selective activation of p53-mediated tumour suppression in high-grade tumours.</strong> Nature 468: 567-571, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21107427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21107427</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21107427[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/nature09526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21107427">Junttila et al. (2010)</a> concluded that p53-mediated tumor suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumor evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11751630+21107427" 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 single endogenous mutant Kras allele is sufficient to promote lung tumor formation in mice, but malignant progression requires additional genetic alterations. <a href="#47" class="mim-tip-reference" title="Junttila, M. R., Karnezis, A. N., Garcia, D., Madriles, F., Kortlever, R. M., Rostker, F., Swigart, L. B., Pham, D. M., Seo, Y., Evan, G. I., Martins, C. P. <strong>Selective activation of p53-mediated tumour suppression in high-grade tumours.</strong> Nature 468: 567-571, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21107427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21107427</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21107427[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/nature09526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21107427">Junttila et al. (2010)</a> showed that advanced lung tumors from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) (see <a href="#0005">190070.0005</a>) allelic enrichment (Kras(G12D)/Kras(wildtype) greater than 1), implying that mutant Kras copy gains are positively selected during progression. Through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, <a href="#49" class="mim-tip-reference" title="Kerr, E. M., Gaude, E., Turrell, F. K., Frezza, C., Martins, C. P. <strong>Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities.</strong> Nature 531: 110-113, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26909577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26909577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26909577[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/nature16967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26909577">Kerr et al. (2016)</a> demonstrated that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channeling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous nonsmall cell lung cancer cells and in vivo, and in spontaneous advanced murine lung tumors (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumors (Kras(G12D) heterozygous). Finally, <a href="#49" class="mim-tip-reference" title="Kerr, E. M., Gaude, E., Turrell, F. K., Frezza, C., Martins, C. P. <strong>Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities.</strong> Nature 531: 110-113, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26909577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26909577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26909577[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/nature16967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26909577">Kerr et al. (2016)</a> demonstrated that mutant Kras copy gain creates unique metabolic dependencies that can be exploited to selectively target these aggressive mutant Kras tumors. The authors concluded that mutant Kras lung tumors are not a single disease but rather a heterogeneous group comprising 2 classes of tumors with distinct metabolic profiles, prognosis, and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26909577+21107427" 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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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>28 Selected Examples</a>):</strong>
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<a href="/allelicVariants/190070" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=190070[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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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> rs121913530 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913530;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/rs121913530?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=rs121913530" 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=rs121913530" 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=RCV000013406 OR RCV000038265 OR RCV000119791 OR RCV000431049 OR RCV001292543 OR RCV001355787 OR RCV003654176 OR RCV003996092 OR RCV004668721" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013406, RCV000038265, RCV000119791, RCV000431049, RCV001292543, RCV001355787, RCV003654176, RCV003996092, RCV004668721" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013406...</a>
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<p>In a cell line of human lung cancer (<a href="/entry/211980">211980</a>), <a href="#66" class="mim-tip-reference" title="Nakano, H., Yamamoto, F., Neville, C., Evans, D., Mizuno, T., Perucho, M. <strong>Isolation of transforming sequences of two human lung carcinomas: structural and functional analysis of the activated c-K-ras oncogenes.</strong> Proc. Nat. Acad. Sci. 81: 71-75, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6320174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6320174</a>] [<a href="https://doi.org/10.1073/pnas.81.1.71" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6320174">Nakano et al. (1984)</a> identified a 34G-T transversion in exon 1 of the KRAS2 gene, resulting in a gly12-to-cys (G12C) substitution. Studies of the mutant protein showed that it had transforming abilities consistent with activation of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6320174" 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 study of 106 prospectively enrolled patients with primary adenocarcinoma of the lung, <a href="#1" class="mim-tip-reference" title="Ahrendt, S. A., Decker, P. A., Alawi, E. A., Zhu, Y., Sanchez-Cespedes, M., Yang, S. C., Haasler, G. B., Kajdacsy-Balla, A., Demeure, M. J., Sidransky, D. <strong>Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung.</strong> Cancer 92: 1525-1530, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11745231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11745231</a>] [<a href="https://doi.org/10.1002/1097-0142(20010915)92:6<1525::aid-cncr1478>3.0.co;2-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11745231">Ahrendt et al. (2001)</a> found that 92 (87%) were smokers. KRAS2 mutations were detected in 40 of 106 tumors (38%) and were significantly more common in smokers compared with nonsmokers (43% vs 0%; P = 0.001). Thirty-nine of the 40 tumors with KRAS2 mutations had 1 of 4 changes in codon 12, the most common being G12C, which was present in 25 tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11745231" 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>Inhibitor of KRAS(G12C)</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., Lanman, B. A., Werner, J., and 22 others. <strong>The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.</strong> Nature 575: 217-223, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31666701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31666701</a>] [<a href="https://doi.org/10.1038/s41586-019-1694-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31666701">Canon et al. (2019)</a> optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity to knockdown KRAS carrying the G12C variant. <a href="#17" class="mim-tip-reference" title="Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., Lanman, B. A., Werner, J., and 22 others. <strong>The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.</strong> Nature 575: 217-223, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31666701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31666701</a>] [<a href="https://doi.org/10.1038/s41586-019-1694-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31666701">Canon et al. (2019)</a> discovered the KRAS(G12C) inhibitor AMG-510 and presented data on its preclinical activity. Treatment with AMG-510 led to the regression of KRAS(G12C) tumors and improved the antitumor efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG-510 resulted in a proinflammatory tumor microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS(G12D) tumors, which suggested adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG-510 demonstrated antitumor activity in the first dosing cohorts and represented a potentially transformative therapy for patients for whom effective treatments are lacking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31666701" 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="#44" class="mim-tip-reference" title="Janne, P. A., Riely, G. J., Gadgeel, S. M., Heist, R. S., Ou, S. I., Pacheco, J. M., Johnson, M. L., Sabari, J. K., Leventakos, K., Yau, E., Bazhenova, L., Negrao, M. V., and 10 others. <strong>Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation.</strong> New Eng. J. Med 387: 120-131, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35658005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35658005</a>] [<a href="https://doi.org/10.1056/NEJMoa2204619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35658005">Janne et al. (2022)</a> conducted a phase 2 cohort study to evaluate the clinical efficacy of oral adagrasib, a selective covalent KRAS(G12C) inhibitor, among patients with KRAS(G12C)-mutated nonsmall cell lung cancer who were previously treated with platinum-based chemotherapy and antiprogrammed death 1 or programmed ligand 1 therapy. Among the 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response by blinded independent review. The median duration of response was 8.5 months, with a median progression-free survival of 6.5 months and median overall survival of 12.6 months at last follow-up. Treatment-related adverse events of grade 3 or higher occurred in 44.8%, resulting in a treatment discontinuation rate of 6.9%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35658005" 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>.0002 LUNG CANCER, SQUAMOUS CELL, SOMATIC</strong>
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BLADDER CANCER, SOMATIC, INCLUDED
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KRAS, GLY12ARG
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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> rs121913530 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913530;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/rs121913530?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=rs121913530" 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=rs121913530" 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=RCV000013407 OR RCV000013408 OR RCV000154401 OR RCV001356365 OR RCV002513010 OR RCV004668722 OR RCV004813033" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013407, RCV000013408, RCV000154401, RCV001356365, RCV002513010, RCV004668722, RCV004813033" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013407...</a>
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<p>In a squamous cell lung carcinoma (<a href="/entry/211980">211980</a>) from a 66-year-old man, <a href="#85" class="mim-tip-reference" title="Santos, E., Martin-Zanca, D., Reddy, E. P., Pierotti, M. A., Della Porta, G., Barbacid, M. <strong>Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient.</strong> Science 223: 661-664, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6695174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6695174</a>] [<a href="https://doi.org/10.1126/science.6695174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6695174">Santos et al. (1984)</a> identified a G-to-C transversion in exon 1 of the KRAS2 gene, resulting in a gly12-to-arg (G12R) substitution. The mutation was not identified in the patient's normal bronchial and pulmonary parenchymal tissues or blood lymphocytes. This mutation had previously been identified in a bladder cancer (<a href="/entry/109800">109800</a>) and a lung cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6695174" 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> rs112445441 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs112445441;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/rs112445441?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=rs112445441" 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=rs112445441" 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=RCV000013409 OR RCV000038269 OR RCV000144967 OR RCV000144968 OR RCV000791297 OR RCV001092389 OR RCV001266168 OR RCV001526657 OR RCV001813183 OR RCV001839444 OR RCV001857340 OR RCV004549358 OR RCV004668723 OR RCV004813034" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013409, RCV000038269, RCV000144967, RCV000144968, RCV000791297, RCV001092389, RCV001266168, RCV001526657, RCV001813183, RCV001839444, RCV001857340, RCV004549358, RCV004668723, RCV004813034" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013409...</a>
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<p><strong><em>Breast Adenocarcinoma, Somatic</em></strong></p><p>
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In a cell line from a human breast adenocarcinoma (<a href="/entry/114480">114480</a>), <a href="#51" class="mim-tip-reference" title="Kozma, S. C., Bogaard, M. E., Buser, K., Saurer, S. M., Bos, J. L., Groner, B., Hynes, N. E. <strong>The human c-Kirsten ras gene is activated by a novel mutation in codon 13 in the breast carcinoma cell line MDA-MB231.</strong> Nucleic Acids Res. 15: 5963-5971, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3627975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3627975</a>] [<a href="https://doi.org/10.1093/nar/15.15.5963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3627975">Kozma et al. (1987)</a> identified a heterozygous G-to-A transition in exon 1 of the KRAS2 gene, resulting in a gly13-to-asp (G13D) substitution and activation of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3627975" 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>Juvenile Myelomonocytic Leukemia, Somatic</em></strong></p><p>
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In white blood cells derived from a 7-month-old girl with juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>), <a href="#58" class="mim-tip-reference" title="Matsuda, K., Shimada, A., Yoshida, N., Ogawa, A., Watanabe, A., Yajima, S., Iizuka, S., Koike, K., Yanai, F., Kawasaki, K., Yanagimachi, M., Kikuchi, A., and 10 others. <strong>Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations.</strong> Blood 109: 5477-5480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332249</a>] [<a href="https://doi.org/10.1182/blood-2006-09-046649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17332249">Matsuda et al. (2007)</a> identified a somatic heterozygous G13D mutation in the KRAS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17332249" 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>RAS-associated Autoimmune Leukoproliferative Disorder, Somatic</em></strong></p><p>
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In 2 unrelated children with RAS-associated autoimmune leukoproliferative disorder (RALD; <a href="/entry/614470">614470</a>), <a href="#94" class="mim-tip-reference" title="Takagi, M., Shinoda, K., Piao, J., Mitsuiki, N., Takagi, M., Matsuda, K., Muramatsu, H., Doisaki, S., Nagasawa, M., Morio, T., Kasahara, Y., Koike, K., Kojima, S., Takao, A., Mizutani, S. <strong>Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation.</strong> Blood 117: 2887-2890, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21063026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21063026</a>] [<a href="https://doi.org/10.1182/blood-2010-08-301515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21063026">Takagi et al. (2011)</a> identified a somatic heterozygous G13D mutation in the KRAS gene. The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. <a href="#94" class="mim-tip-reference" title="Takagi, M., Shinoda, K., Piao, J., Mitsuiki, N., Takagi, M., Matsuda, K., Muramatsu, H., Doisaki, S., Nagasawa, M., Morio, T., Kasahara, Y., Koike, K., Kojima, S., Takao, A., Mizutani, S. <strong>Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation.</strong> Blood 117: 2887-2890, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21063026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21063026</a>] [<a href="https://doi.org/10.1182/blood-2010-08-301515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21063026">Takagi et al. (2011)</a> noted that the same somatic mutation had been found in patients with JMML, and they postulated that the variable clinical and hematologic features of the 2 disorders may be related to the stage of differentiation at which the KRAS mutation is acquired. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21063026" 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>Oculoectodermal Syndrome</em></strong></p><p>
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In a patient (patient 1) with oculoectodermal syndrome (OES; <a href="/entry/600268">600268</a>), <a href="#75" class="mim-tip-reference" title="Peacock, J. D., Dykema, K. J., Toriello, H. V., Mooney, M. R., Scholten, D. J., II, Winn, M. E., Borgman, A., Duesbery, N. S., Hiemenga, J. A., Liu, C., Campbell, S., Nickoloff, B. P., Williams, B. O., Steensma, M. <strong>Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations.</strong> Am. J. Med. Genet. 167A: 1429-1435, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25808193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25808193</a>] [<a href="https://doi.org/10.1002/ajmg.a.37048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25808193">Peacock et al. (2015)</a> performed whole-genome shotgun sequencing to compare DNA from the patient's femur nonossifying fibroma (NOF) with DNA from her peripheral blood, and identified the G13D mutation (c.38G-A, NM_033360.3) in the KRAS gene. The mutation was confirmed by both Sanger and next-generation sequencing (allelic frequency, 32.9%). The mutation was also detectable in her hyperpigmented skin, periosteum, muscle, and humerus NOF samples (allelic frequencies, 10.3-38.8%), but not in her bone marrow or peripheral blood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25808193" 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>.0004 BLADDER CANCER, TRANSITIONAL CELL, SOMATIC</strong>
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KRAS, ALA59THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913528 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913528;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=rs121913528" 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=rs121913528" 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=RCV000013410" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013410" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013410</a>
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<p>In a human transitional cell bladder carcinoma cell line (<a href="/entry/109800">109800</a>), <a href="#33" class="mim-tip-reference" title="Grimmond, S. M., Raghavan, D., Russell, P. J. <strong>Detection of a rare point mutation in Ki-ras of a human bladder cancer xenograft by polymerase chain reaction and direct sequencing.</strong> Urol. Res. 20: 121-126, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1553789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1553789</a>] [<a href="https://doi.org/10.1007/BF00296523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1553789">Grimmond et al. (1992)</a> identified a heterozygous G-to-A transition in the KRAS2 gene, resulting in an ala59-to-thr (A59T) substitution. The mutation was present in paraffin-embedded tissue from the primary tumor of the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1553789" 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>.0005 PANCREATIC CARCINOMA, SOMATIC</strong>
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GASTRIC CANCER, SOMATIC, INCLUDED<br />
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EPIDERMAL NEVUS, SOMATIC, INCLUDED<br />
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NEVUS SEBACEOUS, SOMATIC, INCLUDED<br />
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SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC, INCLUDED<br />
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JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED<br />
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RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, 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> rs121913529 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913529;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/rs121913529?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=rs121913529" 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=rs121913529" 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=RCV000013411 OR RCV000022799 OR RCV000029214 OR RCV000029215 OR RCV000144969 OR RCV000144970 OR RCV000150896 OR RCV000150897 OR RCV000272938 OR RCV000433573 OR RCV000548006 OR RCV000585796 OR RCV000662266 OR RCV000856666 OR RCV001799604 OR RCV001839445 OR RCV002508117 OR RCV003327361 OR RCV004018620 OR RCV004554600 OR RCV004668724 OR RCV005007840" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013411, RCV000022799, RCV000029214, RCV000029215, RCV000144969, RCV000144970, RCV000150896, RCV000150897, RCV000272938, RCV000433573, RCV000548006, RCV000585796, RCV000662266, RCV000856666, RCV001799604, RCV001839445, RCV002508117, RCV003327361, RCV004018620, RCV004554600, RCV004668724, RCV005007840" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013411...</a>
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<p><strong><em>Pancreatic Carcinoma, Somatic</em></strong></p><p>
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<a href="#64" class="mim-tip-reference" title="Motojima, K., Urano, T., Nagata, Y., Shiku, H., Tsurifune, T., Kanematsu, T. <strong>Detection of point mutations in the Kirsten-ras oncogene provides evidence for the multicentricity of pancreatic carcinoma.</strong> Ann. Surg. 217: 138-143, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8439212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8439212</a>] [<a href="https://doi.org/10.1097/00000658-199302000-00007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8439212">Motojima et al. (1993)</a> identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (<a href="/entry/260350">260350</a>). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; <a href="#0006">190070.0006</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8439212" 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>Gastric Cancer, Somatic</em></strong></p><p>
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<a href="#55" class="mim-tip-reference" title="Lee, K.-H., Lee, J.-S., Suh, C., Kim, S.-W., Kim, S.-B., Lee, J.-H., Lee, M.-S., Park, M.-Y., Sun, H.-S., Kim, S.-H. <strong>Clinicopathologic significance of the K-ras gene codon 12 point mutation in stomach cancer: an analysis of 140 cases.</strong> Cancer 75: 2794-2801, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7773929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7773929</a>] [<a href="https://doi.org/10.1002/1097-0142(19950615)75:12<2794::aid-cncr2820751203>3.0.co;2-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7773929">Lee et al. (1995)</a> found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (<a href="/entry/613659">613659</a>); 2 cases had G12D. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7773929" 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>Epidermal Nevus, Somatic</em></strong></p><p>
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<a href="#14" class="mim-tip-reference" title="Bourdeaut, F., Herault, A., Gentien, D., Pierron, G., Ballet, S., Reynaud, S., Paris, R., Schleiermacher, G., Baumann, C., Philippe-Chomette, P., Gauthier-Villars, M., Peuchmaur, M., Radvanyi, F., Delattre, O. <strong>Mosaicism for oncogenic G12D KRAS mutation associated with epidermal nevus, polycystic kidneys and rhabdomyosarcoma.</strong> J. Med. Genet. 47: 859-862, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20805368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20805368</a>] [<a href="https://doi.org/10.1136/jmg.2009.075374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20805368">Bourdeaut et al. (2010)</a> found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (<a href="/entry/162900">162900</a>) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20805368" 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="Hafner, C., Toll, A., Gantner, S., Mauerer, A., Lurkin, I., Acquadro, F., Fernandez-Casado, A., Zwarthoff, E. C., Dietmaier, W., Baselga, E., Parera, E., Vicente, A., Casanova, A., Cigudosa, J., Mentzel, T., Pujol, R. M., Landthaler, M., Real, F. X. <strong>Keratinocytic epidermal nevi are associated with mosaic RAS mutations.</strong> J. Med. Genet. 49: 249-253, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22499344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22499344</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22499344">Hafner et al. (2012)</a> identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22499344" 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>Nevus Sebaceous, Somatic</em></strong></p><p>
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<a href="#34" class="mim-tip-reference" title="Groesser, L., Herschberger, E., Ruetten, A., Ruivenkamp, C., Lopriore, E., Zutt, M., Langmann, T., Singer, S., Klingseisen, L., Schneider-Brachert, W., Toll, A., Real, F. X., Landthaler, M., Hafner, C. <strong>Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.</strong> Nature Genet. 44: 783-787, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683711</a>] [<a href="https://doi.org/10.1038/ng.2316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683711">Groesser et al. (2012)</a> identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see <a href="/entry/162900">162900</a>). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; <a href="/entry/190020#0017">190020.0017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22683711" 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>Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic</em></strong></p><p>
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The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (<a href="/entry/163200">163200</a>) who was originally reported by <a href="#82" class="mim-tip-reference" title="Rijntjes-Jacobs, E. G. J., Lopriore, E., Steggerda, S. J., Kant, S. G. <strong>Walther, F. J.: Discordance for Schimmelpenning-Feuerstein-Mims syndrome in monochorionic twins supports the concept of a postzygotic mutation.</strong> Am. J. Med. Genet. 152A: 2816-2819, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20949522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20949522</a>] [<a href="https://doi.org/10.1002/ajmg.a.33635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20949522">Rijntjes-Jacobs et al. (2010)</a>. <a href="#34" class="mim-tip-reference" title="Groesser, L., Herschberger, E., Ruetten, A., Ruivenkamp, C., Lopriore, E., Zutt, M., Langmann, T., Singer, S., Klingseisen, L., Schneider-Brachert, W., Toll, A., Real, F. X., Landthaler, M., Hafner, C. <strong>Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.</strong> Nature Genet. 44: 783-787, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683711</a>] [<a href="https://doi.org/10.1038/ng.2316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683711">Groesser et al. (2012)</a> postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22683711+20949522" 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>Juvenile Myelomonocytic Leukemia, Somatic</em></strong></p><p>
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In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>), <a href="#58" class="mim-tip-reference" title="Matsuda, K., Shimada, A., Yoshida, N., Ogawa, A., Watanabe, A., Yajima, S., Iizuka, S., Koike, K., Yanai, F., Kawasaki, K., Yanagimachi, M., Kikuchi, A., and 10 others. <strong>Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations.</strong> Blood 109: 5477-5480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332249</a>] [<a href="https://doi.org/10.1182/blood-2006-09-046649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17332249">Matsuda et al. (2007)</a> identified a somatic heterozygous G12D mutation in the KRAS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17332249" 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>RAS-associated Autoimmune Leukoproliferative Disorder, Somatic</em></strong></p><p>
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In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; <a href="/entry/614470">614470</a>), <a href="#67" class="mim-tip-reference" title="Niemela, J. E., Lu, L., Fleisher, T. A., Davis, J., Caminha, I., Natter, M., Beer, L. A., Dowdell, K. C., Pittaluga, S., Raffeld, M., Rao, V. K., Oliveira, J. B. <strong>Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.</strong> Blood 117: 2883-2886, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21079152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21079152</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21079152[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/10.1182/blood-2010-07-295501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21079152">Niemela et al. (2010)</a> identified a somatic heterozygous G12D mutation in the KRAS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21079152" 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>.0006 PANCREATIC CARCINOMA, 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> rs121913529 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913529;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/rs121913529?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=rs121913529" 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=rs121913529" 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=RCV000013413 OR RCV000029216 OR RCV000150895 OR RCV000154262 OR RCV000157944 OR RCV000585801 OR RCV002291496 OR RCV003322589 OR RCV003455987 OR RCV003539760 OR RCV004668725" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013413, RCV000029216, RCV000150895, RCV000154262, RCV000157944, RCV000585801, RCV002291496, RCV003322589, RCV003455987, RCV003539760, RCV004668725" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013413...</a>
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<p><strong><em>Pancreatic Carcinoma, Somatic</em></strong></p><p>
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For discussion of the gly12-to-val (G12V) substitution that was found in 1 of 53 pancreatic carcinomas (<a href="/entry/260350">260350</a>) by <a href="#64" class="mim-tip-reference" title="Motojima, K., Urano, T., Nagata, Y., Shiku, H., Tsurifune, T., Kanematsu, T. <strong>Detection of point mutations in the Kirsten-ras oncogene provides evidence for the multicentricity of pancreatic carcinoma.</strong> Ann. Surg. 217: 138-143, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8439212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8439212</a>] [<a href="https://doi.org/10.1097/00000658-199302000-00007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8439212">Motojima et al. (1993)</a>, see <a href="#0005">190070.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8439212" 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>Nevus Sebaceous, Somatic</em></strong></p><p>
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<a href="#34" class="mim-tip-reference" title="Groesser, L., Herschberger, E., Ruetten, A., Ruivenkamp, C., Lopriore, E., Zutt, M., Langmann, T., Singer, S., Klingseisen, L., Schneider-Brachert, W., Toll, A., Real, F. X., Landthaler, M., Hafner, C. <strong>Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.</strong> Nature Genet. 44: 783-787, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683711</a>] [<a href="https://doi.org/10.1038/ng.2316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683711">Groesser et al. (2012)</a> identified a somatic G12V mutation in 1 (2%) of 65 nevus sebaceous tumors (see <a href="/entry/162900">162900</a>). The tumor also carried a somatic mutation in the HRAS gene (G13R; <a href="/entry/190020#0017">190020.0017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22683711" 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> rs121913530 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913530;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/rs121913530?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=rs121913530" 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=rs121913530" 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=RCV000013414 OR RCV000038264 OR RCV000119790 OR RCV000144971 OR RCV000782191 OR RCV001851824 OR RCV004562205 OR RCV004668726 OR RCV004795403" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013414, RCV000038264, RCV000119790, RCV000144971, RCV000782191, RCV001851824, RCV004562205, RCV004668726, RCV004795403" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013414...</a>
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<p><strong><em>Gastric Cancer, Somatic</em></strong></p><p>
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<a href="#55" class="mim-tip-reference" title="Lee, K.-H., Lee, J.-S., Suh, C., Kim, S.-W., Kim, S.-B., Lee, J.-H., Lee, M.-S., Park, M.-Y., Sun, H.-S., Kim, S.-H. <strong>Clinicopathologic significance of the K-ras gene codon 12 point mutation in stomach cancer: an analysis of 140 cases.</strong> Cancer 75: 2794-2801, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7773929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7773929</a>] [<a href="https://doi.org/10.1002/1097-0142(19950615)75:12<2794::aid-cncr2820751203>3.0.co;2-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7773929">Lee et al. (1995)</a> found mutations in codon 12 of the KRAS2 gene in 9 of 140 cases of gastric cancer (<a href="/entry/613659">613659</a>); 7 cases had a G-to-A transition, resulting in a gly12-to-ser (G12S) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7773929" 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>Juvenile Myelomonocytic Leukemia, Somatic</em></strong></p><p>
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In white blood cells derived from a 4-month-old girl with juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>), <a href="#58" class="mim-tip-reference" title="Matsuda, K., Shimada, A., Yoshida, N., Ogawa, A., Watanabe, A., Yajima, S., Iizuka, S., Koike, K., Yanai, F., Kawasaki, K., Yanagimachi, M., Kikuchi, A., and 10 others. <strong>Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations.</strong> Blood 109: 5477-5480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332249</a>] [<a href="https://doi.org/10.1182/blood-2006-09-046649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17332249">Matsuda et al. (2007)</a> identified a somatic heterozygous G12S mutation in the KRAS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17332249" 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 LEUKEMIA, ACUTE MYELOGENOUS, 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">rs606231202 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231202;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=rs606231202" 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=rs606231202" 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=RCV000013415" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013415" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013415</a>
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<p>In the bone marrow of a 4-year-old child with acute myeloid leukemia (AML; <a href="/entry/601626">601626</a>), <a href="#12" class="mim-tip-reference" title="Bollag, G., Adler, F., elMasry, N., McCabe, P. C., Connor, E., Jr., Thompson, P., McCormick, F., Shannon, K. <strong>Biochemical characterization of a novel KRAS insertion mutation from a human leukemia.</strong> J. Biol. Chem. 271: 32491-32494, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8955068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8955068</a>] [<a href="https://doi.org/10.1074/jbc.271.51.32491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8955068">Bollag et al. (1996)</a> identified an in-frame 3-bp insertion in exon 1 of the KRAS2 gene, resulting in an insertion of gly11. Expression of the mutant protein in NIH 3T3 cells caused cellular transformation, and expression in COS cells activated the RAS-mitogen-activated protein kinase signaling pathway. RAS-GTP levels measured in COS cells established that this novel mutant accumulates up to 90% in the GTP state, considerably higher than a residue 12 mutant. This mutation was the first dominant RAS mutation found in human cancer that did not involve residues 12, 13, or 61. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8955068" 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 CARDIOFACIOCUTANEOUS SYNDROME 2</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">rs104894359 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894359;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=rs104894359" 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=rs104894359" 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=RCV000013416 OR RCV000157935 OR RCV000254661 OR RCV000521390 OR RCV000844635 OR RCV001267316 OR RCV003313917" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013416, RCV000157935, RCV000254661, RCV000521390, RCV000844635, RCV001267316, RCV003313917" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013416...</a>
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<p>In an individual with cardiofaciocutaneous syndrome (CFC2; <a href="/entry/615278">615278</a>), <a href="#68" 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> identified a heterozygous 178G-C transversion in exon 2 of the KRAS2 gene, predicting a gly60-to-arg (G60R) substitution. <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">rs104894360 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894360;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=rs104894360" 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=rs104894360" 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=RCV000013417 OR RCV000013418 OR RCV000157940 OR RCV000212501 OR RCV000507330 OR RCV000523200 OR RCV000763307 OR RCV000844634 OR RCV003450634 OR RCV004018621" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013417, RCV000013418, RCV000157940, RCV000212501, RCV000507330, RCV000523200, RCV000763307, RCV000844634, RCV003450634, RCV004018621" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013417...</a>
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<p><strong><em>Cardiofaciocutaneous Syndrome 2</em></strong></p><p>
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In 2 unrelated individuals with cardiofaciocutaneous syndrome (CFC2; <a href="/entry/615278">615278</a>), <a href="#68" 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> identified a heterozygous 458A-T transversion in exon 4b of the KRAS2 gene, predicting an asp153-to-val (D153V) substitution. The D153V mutation was identified in DNA extracted from both blood and buccal cells of 1 of the individuals. This heterozygous mutation and G60R (<a href="#0009">190070.0009</a>) were not found in 100 control chromosomes and were not found in any parent. The results suggested that these germline mutations occurred de novo. <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><strong><em>Noonan Syndrome 3</em></strong></p><p>
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<a href="#86" class="mim-tip-reference" title="Schubbert, S., Zenker, M., Rowe, S. L., Boll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., Nguyen, H., West, B., Zhang, K. Y. J., Sistermans, E., Rauch, A., Niemeyer, C. M., Shannon, K., Kratz, C. P. <strong>Germline KRAS mutations cause Noonan syndrome.</strong> Nature Genet. 38: 331-336, 2006. Note: Erratum: Nature Genet. 38: 598 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474405</a>] [<a href="https://doi.org/10.1038/ng1748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474405">Schubbert et al. (2006)</a> found the D153V mutation in a patient who had been diagnosed with Noonan syndrome-3 (NS3; <a href="/entry/609942">609942</a>). The 18-year-old male had hypertrophic cardiomyopathy, dysplastic mitral valve with prolapse, Noonan-like features, short stature, mild pectus carinatum, unilateral cryptorchidism, mild developmental delay, and grand mal seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474405" 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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KRAS, THR58ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894364 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894364;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=rs104894364" 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=rs104894364" 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=RCV000013419 OR RCV000157933 OR RCV000211785 OR RCV000704828" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013419, RCV000157933, RCV000211785, RCV000704828" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013419...</a>
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<p>In a 3-month-old female with Noonan syndrome-3 (NS3; <a href="/entry/609942">609942</a>), <a href="#86" class="mim-tip-reference" title="Schubbert, S., Zenker, M., Rowe, S. L., Boll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., Nguyen, H., West, B., Zhang, K. Y. J., Sistermans, E., Rauch, A., Niemeyer, C. M., Shannon, K., Kratz, C. P. <strong>Germline KRAS mutations cause Noonan syndrome.</strong> Nature Genet. 38: 331-336, 2006. Note: Erratum: Nature Genet. 38: 598 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474405</a>] [<a href="https://doi.org/10.1038/ng1748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474405">Schubbert et al. (2006)</a> identified a heterozygous 173C-T transition in the KRAS2 gene, resulting in a thr58-to-ile (T58I) substitution. The child had a severe clinical phenotype and presented with a myeloproliferative disorder of the juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>) type. The mutation was present in the patient's buccal cells but was absent in parental DNA. Clinical features included atrial septal defect, ventricular septal defect, valvular pulmonary stenosis, dysmorphic facial features, short stature, webbed neck, severe developmental delay, macrocephaly, and sagittal suture synostosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474405" 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="Kratz, C. P., Zampino, G., Kriek, M., Kant, S. G., Leoni, C., Pantaleoni, F., Oudesluys-Murphy, A. M., Di Rocco, C., Kloska, S. P., Tartaglia, M., Zenker, M. <strong>Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations.</strong> Am. J. Med. Genet. 149A: 1036-1040, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396835</a>] [<a href="https://doi.org/10.1002/ajmg.a.32786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396835">Kratz et al. (2009)</a> identified a de novo heterozygous T58I mutation in a patient with Noonan syndrome who also had craniosynostosis, suggesting a genotype/phenotype correlation. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19396835" 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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KRAS, VAL14ILE
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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> rs104894365 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894365;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/rs104894365?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=rs104894365" 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=rs104894365" 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=RCV000013420 OR RCV000119792 OR RCV000157945 OR RCV000212499 OR RCV000521254 OR RCV000844637 OR RCV001266727 OR RCV001813184" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013420, RCV000119792, RCV000157945, RCV000212499, RCV000521254, RCV000844637, RCV001266727, RCV001813184" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013420...</a>
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<p>In 3 unrelated patients with Noonan syndrome-3 (NS3; <a href="/entry/609942">609942</a>), <a href="#86" class="mim-tip-reference" title="Schubbert, S., Zenker, M., Rowe, S. L., Boll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., Nguyen, H., West, B., Zhang, K. Y. J., Sistermans, E., Rauch, A., Niemeyer, C. M., Shannon, K., Kratz, C. P. <strong>Germline KRAS mutations cause Noonan syndrome.</strong> Nature Genet. 38: 331-336, 2006. Note: Erratum: Nature Genet. 38: 598 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474405</a>] [<a href="https://doi.org/10.1038/ng1748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474405">Schubbert et al. (2006)</a> identified a heterozygous 40G-A transition in the KRAS2 gene, resulting in a val14-to-ile (V14I) substitution. Each individual showed a mild clinical phenotype, and none had a history of myeloproliferative disorder or cancer. The patients were from a group of Noonan syndrome patients studied who did not have mutation in the PTPN11 gene (<a href="/entry/176876">176876</a>) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474405" 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">rs104894366 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894366;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=rs104894366" 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=rs104894366" 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=RCV000043674 OR RCV000207495 OR RCV000211723 OR RCV000850569 OR RCV001851825" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043674, RCV000207495, RCV000211723, RCV000850569, RCV001851825" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043674...</a>
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<p>In a 13-year-old female with the diagnosis of cardiofaciocutaneous syndrome (CFC2; <a href="/entry/615278">615278</a>), <a href="#86" class="mim-tip-reference" title="Schubbert, S., Zenker, M., Rowe, S. L., Boll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., Nguyen, H., West, B., Zhang, K. Y. J., Sistermans, E., Rauch, A., Niemeyer, C. M., Shannon, K., Kratz, C. P. <strong>Germline KRAS mutations cause Noonan syndrome.</strong> Nature Genet. 38: 331-336, 2006. Note: Erratum: Nature Genet. 38: 598 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474405</a>] [<a href="https://doi.org/10.1038/ng1748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474405">Schubbert et al. (2006)</a> found a heterozygous pro34-to-arg (P34R) mutation in the KRAS2 gene. The patient had pulmonic stenosis, left ventricular hypertrophy, Noonan-like facial features, short stature, short neck, broad thorax, lymphedema, chylothorax, left ptosis, severe developmental delay, and agenesis of the corpus callosum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474405" 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">rs104894367 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894367;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=rs104894367" 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=rs104894367" 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=RCV000013422" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013422" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013422</a>
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<p>In a 1-year-old girl with the diagnosis of Noonan syndrome-3 (NS3; <a href="/entry/609942">609942</a>), <a href="#19" class="mim-tip-reference" title="Carta, C., Pantaleoni, F., Bocchinfuso, G., Stella, L., Vasta, I., Sarkozy, A., Digilio, C., Palleschi, A., Pizzuti, A., Grammatico, P., Zampino, G., Dallapiccola, B., Gelb, B. D., Tartaglia, M. <strong>Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype.</strong> Am. J. Hum. Genet. 79: 129-135, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16773572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16773572</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16773572[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/10.1086/504394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16773572">Carta et al. (2006)</a> identified a 455T-G transversion in the KRAS2 gene, resulting in a val152-to-gly (V152G) substitution. The patient had macrocephaly with high and broad forehead, curly and sparse hair, hypertelorism, strabismus, epicanthic folds, downslanting palpebral fissures, hypoplastic nasal bridge with bulbous tip of the nose, high palate and macroglossia, low-set and posteriorly rotated ears, short neck with redundant skin, wide-set nipples, and umbilical hernia. She had been born at 32 weeks' gestation by cesarean section after a pregnancy complicated by a cystic hygroma detected at 12 weeks and polyhydramnios at 30 weeks. At birth she showed edema of the lower limbs. The phenotype showed features overlapping Costello syndrome (<a href="/entry/218040">218040</a>) (polyhydramnios, neonatal macrosomia, and macrocephaly, loose skin, and severe failure to thrive) and, to a lesser extent, CFC syndrome (<a href="/entry/615278">615278</a>) (macrocephaly and sparse hair). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16773572" 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="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013417 OR RCV000013418 OR RCV000157940 OR RCV000212501 OR RCV000507330 OR RCV000523200 OR RCV000763307 OR RCV000844634 OR RCV003450634 OR RCV004018621" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013417, RCV000013418, RCV000157940, RCV000212501, RCV000507330, RCV000523200, RCV000763307, RCV000844634, RCV003450634, RCV004018621" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013417...</a>
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<p>In a 14-year-old girl with Noonan syndrome-3 (NS3; <a href="/entry/609942">609942</a>) and some features of CFC syndrome (<a href="/entry/615278">615278</a>), <a href="#19" class="mim-tip-reference" title="Carta, C., Pantaleoni, F., Bocchinfuso, G., Stella, L., Vasta, I., Sarkozy, A., Digilio, C., Palleschi, A., Pizzuti, A., Grammatico, P., Zampino, G., Dallapiccola, B., Gelb, B. D., Tartaglia, M. <strong>Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype.</strong> Am. J. Hum. Genet. 79: 129-135, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16773572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16773572</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16773572[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/10.1086/504394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16773572">Carta et al. (2006)</a> identified a 458A-T transversion in the KRAS2 gene, resulting in an asp153-to-val (D153V) substitution. The girl had short stature and growth retardation and delayed bone age, cardiac defects (moderate ventricular hypertrophy, mild pulmonic stenosis, and atrial septal defect), dysmorphic features (hypertelorism, downslanting palpebral fissures, strabismus, low-set and thick ears, relative macrocephaly with high forehead, and a depressed nasal bridge), short and mildly webbed neck, wide-set nipples, and developmental delay. There was hyperpigmentation of the skin and a large cafe-au-lait spot on the face. Gestation was complicated by polyhydramnios. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16773572" 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> rs121913535 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913535;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/rs121913535?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=rs121913535" 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=rs121913535" 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=RCV000013424 OR RCV000038267 OR RCV001357137" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013424, RCV000038267, RCV001357137" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013424...</a>
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<p>In 1 of 21 sporadic pilocytic astrocytoma (PA) (see <a href="/entry/137800">137800</a>) samples, <a href="#88" class="mim-tip-reference" title="Sharma, M. K., Zehnbauer, B. A., Watson, M. A., Gutmann, D. H. <strong>RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma.</strong> Neurology 65: 1335-1336, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16247081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16247081</a>] [<a href="https://doi.org/10.1212/01.wnl.0000180409.78098.d7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16247081">Sharma et al. (2005)</a> identified a G-to-C transversion in the KRAS2 gene, resulting in a gly13-to-arg (G13R) substitution. The tumor arose in the cortex of an 11-year-old boy; the mutation was not identified in the germline of the patient. Immunohistochemical studies showed increased phospho-AKT (see <a href="/entry/164730">164730</a>) activity compared to controls in all 21 PA samples, indicating increased activation of the Ras pathway. No mutations in the KRAS gene were observed in the other tumors, and none of the 21 tumors showed mutations in the HRAS (<a href="/entry/190020">190020</a>) or NRAS (<a href="/entry/164790">164790</a>) genes. Of note, the G13R substitution occurs in the same codon as another KRAS mutation (G13D; <a href="#0003">190070.0003</a>) identified in a breast carcinoma cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16247081" 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> rs104894361 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894361;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/rs104894361?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=rs104894361" 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=rs104894361" 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=RCV000013425 OR RCV000153427 OR RCV000520745 OR RCV000623267" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013425, RCV000153427, RCV000520745, RCV000623267" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013425...</a>
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<p>In a 7.5-month-old male infant with a clinical diagnosis of Costello syndrome (<a href="/entry/218040">218040</a>), <a href="#108" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. <strong>Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.</strong> J. Med. Genet. 44: 131-135, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17056636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17056636</a>] [<a href="https://doi.org/10.1136/jmg.2006.046300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17056636">Zenker et al. (2007)</a> identified a heterozygous 15A-T transversion in exon 1 of the KRAS2 gene, resulting in a lys5-to-asn (K5N) substitution. The patient had hypertelorism, downslanting palpebral fissures, coarse facies, pectus carinatum, sparse hair, redundant skin, and moderate mental retardation. <a href="#108" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. <strong>Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.</strong> J. Med. Genet. 44: 131-135, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17056636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17056636</a>] [<a href="https://doi.org/10.1136/jmg.2006.046300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17056636">Zenker et al. (2007)</a> noted that the patient may later develop features of cardiofaciocutaneous syndrome (CFC2; <a href="/entry/615278">615278</a>), which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17056636" 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="#48" class="mim-tip-reference" title="Kerr, B., Allanson, J., Delrue, M. A., Gripp, K. W., Lacombe, D., Lin, A. E., Rauen, K. A. <strong>The diagnosis of Costello syndrome: nomenclature in Ras/MAPK pathway disorders. (Letter)</strong> Am. J. Med. Genet. 146A: 1218-1220, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18386799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18386799</a>] [<a href="https://doi.org/10.1002/ajmg.a.32273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18386799">Kerr et al. (2008)</a> commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (<a href="/entry/190020">190020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18386799" 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>.0018 CARDIOFACIOCUTANEOUS SYNDROME 2</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">rs104894362 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894362;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=rs104894362" 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=rs104894362" 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=RCV000013426 OR RCV000157942 OR RCV001205658 OR RCV004549359" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013426, RCV000157942, RCV001205658, RCV004549359" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013426...</a>
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<p>In a male infant with a clinical diagnosis of Costello syndrome (<a href="/entry/218040">218040</a>) who died suddenly at age 14 months, <a href="#108" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. <strong>Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.</strong> J. Med. Genet. 44: 131-135, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17056636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17056636</a>] [<a href="https://doi.org/10.1136/jmg.2006.046300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17056636">Zenker et al. (2007)</a> identified a heterozygous 468C-G transversion in the KRAS2 gene, resulting in a phe156-to-leu (F156L) substitution. The patient had coarse facies, cardiac defects, sparse hair, loose and redundant skin, developmental delay, and moderate mental retardation. <a href="#108" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. <strong>Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.</strong> J. Med. Genet. 44: 131-135, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17056636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17056636</a>] [<a href="https://doi.org/10.1136/jmg.2006.046300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17056636">Zenker et al. (2007)</a> noted that the patient may later develop features of cardiofaciocutaneous syndrome (CFC2; <a href="/entry/615278">615278</a>), which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17056636" 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="#48" class="mim-tip-reference" title="Kerr, B., Allanson, J., Delrue, M. A., Gripp, K. W., Lacombe, D., Lin, A. E., Rauen, K. A. <strong>The diagnosis of Costello syndrome: nomenclature in Ras/MAPK pathway disorders. (Letter)</strong> Am. J. Med. Genet. 146A: 1218-1220, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18386799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18386799</a>] [<a href="https://doi.org/10.1002/ajmg.a.32273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18386799">Kerr et al. (2008)</a> commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (<a href="/entry/190020">190020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18386799" 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">rs193929331 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs193929331;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=rs193929331" 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=rs193929331" 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=RCV000013427 OR RCV000149836 OR RCV000364781 OR RCV000605141 OR RCV002291547 OR RCV004549360" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013427, RCV000149836, RCV000364781, RCV000605141, RCV002291547, RCV004549360" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013427...</a>
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<p>In a 20-year-old woman with clinical features typical of Costello syndrome (<a href="/entry/218040">218040</a>) and additional findings seen in Noonan syndrome (NS3; <a href="/entry/609942">609942</a>), <a href="#8" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Brasil, A. S., Albano, L. M. J., Kim, C. A., Krieger, J. E. <strong>Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene.</strong> J. Hum. Genet. 52: 521-526, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17468812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17468812</a>] [<a href="https://doi.org/10.1007/s10038-007-0146-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17468812">Bertola et al. (2007)</a> identified a 194A-G transition in exon 2 of the KRAS gene, resulting in a lys5-to-glu (K5E) substitution. The mutation was not found in her unaffected mother or brother or in 100 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17468812" 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="#48" class="mim-tip-reference" title="Kerr, B., Allanson, J., Delrue, M. A., Gripp, K. W., Lacombe, D., Lin, A. E., Rauen, K. A. <strong>The diagnosis of Costello syndrome: nomenclature in Ras/MAPK pathway disorders. (Letter)</strong> Am. J. Med. Genet. 146A: 1218-1220, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18386799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18386799</a>] [<a href="https://doi.org/10.1002/ajmg.a.32273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18386799">Kerr et al. (2008)</a> commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (<a href="/entry/190020">190020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18386799" 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="#9" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Brasil, A. S., Suzuki, L., Leite, C., Falzoni, R., Tannuri, U., Poplawski, A. B., Janowski, K. M., Kim, C. A., Messiaen, L. M. <strong>Multiple, diffuse schwannomas in a RASopathy phenotype patient with germline KRAS mutation: a causal relationship? (Letter)</strong> Clin. Genet. 81: 595-597, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22211815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22211815</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01764.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22211815">Bertola et al. (2012)</a> reported a patient with a germline K5E mutation and dysmorphic features who developed multiple diffuse schwannomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22211815" 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">rs104894359 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894359;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=rs104894359" 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=rs104894359" 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=RCV000013428 OR RCV000157934 OR RCV000689097 OR RCV002470709" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013428, RCV000157934, RCV000689097, RCV002470709" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013428...</a>
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<p>In a patient with Noonan syndrome-3 (NS3; <a href="/entry/609942">609942</a>) and craniosynostosis, <a href="#53" class="mim-tip-reference" title="Kratz, C. P., Zampino, G., Kriek, M., Kant, S. G., Leoni, C., Pantaleoni, F., Oudesluys-Murphy, A. M., Di Rocco, C., Kloska, S. P., Tartaglia, M., Zenker, M. <strong>Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations.</strong> Am. J. Med. Genet. 149A: 1036-1040, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396835</a>] [<a href="https://doi.org/10.1002/ajmg.a.32786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396835">Kratz et al. (2009)</a> identified a de novo heterozygous 178G-A transition in the KRAS gene, resulting in a gly60-to-ser (G60S) substitution. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19396835" 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 mutation in this same codon (G60R; <a href="#0009">190070.0009</a>) has been found in a patient with cardiofaciocutaneous syndrome (CFC2; <a href="/entry/615278">615278</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">rs387907205 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907205;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=rs387907205" 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=rs387907205" 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=RCV000024617" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024617" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024617</a>
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<p>In a mother and son with variable features of cardiofaciocutaneous syndrome (CFC2; <a href="/entry/615278">615278</a>), <a href="#93" class="mim-tip-reference" title="Stark, Z., Gillessen-Kaesbach, G., Ryan, M. M., Cirstea, I. C., Gremer, L., Ahmadian, M. R., Savarirayan, R., Zenker, M. <strong>Two novel germline KRAS mutations: expanding the molecular and clinical phenotype.</strong> Clin. Genet. 81: 590-594, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21797849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21797849</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01754.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21797849">Stark et al. (2012)</a> identified a heterozygous 211T-C transition in exon 3 of the KRAS gene, resulting in a tyr71-to-his (Y71H) substitution in a highly conserved residue close to a region that is important for effector and regulator binding. The mutation was not found in 500 control individuals and was shown by in vitro studies to increase effector affinity. The son had delayed psychomotor development and a distinctive appearance, including curly hair, absent eyebrows, and broad forehead. Echocardiogram was normal at age 3 years. His mother had a similar physical appearance and also had high-arched palate, myopia, and mitral valve prolapse. She had attended a school for children with special needs. Both patients showed signs of a peripheral sensorimotor axonal neuropathy, more severe in the mother, who developed Charcot arthropathy of the feet. PMP22 (<a href="/entry/601097">601097</a>) testing in the mother was negative, but an additional cause of the neuropathy could not be excluded. The authors stated that this was the first documented vertically transmitted KRAS mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21797849" 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>Y71 is located at the end of the switch II region of KRAS. Using in vitro assays and transfected COS-7 cells, <a href="#23" class="mim-tip-reference" title="Cirstea, I. C., Gremer, L., Dvorsky, R., Zhang, S.-C., Piekorz, R. P., Zenker, M., Ahmadian, M. R. <strong>Diverging gain-of-function mechanisms of two novel KRAS mutations associated with Noonan and cardio-facio-cutaneous syndromes.</strong> Hum. Molec. Genet. 22: 262-270, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23059812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23059812</a>] [<a href="https://doi.org/10.1093/hmg/dds426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23059812">Cirstea et al. (2013)</a> found that the Y71H mutation increased the binding affinity of KRAS for its major effector, RAF1 kinase (<a href="/entry/164760">164760</a>), leading to increased activation of MEK1 (<a href="/entry/176872">176872</a>)/MEK2 (<a href="/entry/601263">601263</a>) and ERK1 (<a href="/entry/601795">601795</a>)/ERK2 (<a href="/entry/176948">176948</a>), irrespective of stimulation. The mutation did not alter the rate of nucleotide dissociation by KRAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23059812" 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>.0022 CARDIOFACIOCUTANEOUS SYNDROME 2</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">rs387907206 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907206;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=rs387907206" 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=rs387907206" 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=RCV000024618 OR RCV000520244" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024618, RCV000520244" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024618...</a>
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<p>In a girl with variable features of cardiofaciocutaneous syndrome (CFC2; <a href="/entry/615278">615278</a>), <a href="#93" class="mim-tip-reference" title="Stark, Z., Gillessen-Kaesbach, G., Ryan, M. M., Cirstea, I. C., Gremer, L., Ahmadian, M. R., Savarirayan, R., Zenker, M. <strong>Two novel germline KRAS mutations: expanding the molecular and clinical phenotype.</strong> Clin. Genet. 81: 590-594, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21797849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21797849</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01754.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21797849">Stark et al. (2012)</a> identified a de novo heterozygous 439A-G transition in exon 4 of the KRAS gene, resulting in a lys147-to-glu (K147E) substitution in a highly conserved residue close to known mutations. Lys147 is part of a motif involved in the binding network for guanine nucleotides, which determine the activation state of RAS proteins. In vitro studies demonstrated that the K147E mutant protein predominates in the active GTP-bound form, probably due to facilitated uncatalyzed GDP/GTP exchange. The patient was 1 of a female dizygotic twin pair; the other twin was unaffected. The patient had a high birth weight, macrocephaly, and abnormal craniofacial features, including proptosis, hypertelorism, downslanting palpebral fissures, low-set ears, and short neck, suggestive of Noonan syndrome. Reexamination at age 3.5 years showed coarser facial features more consistent with CFC. She also had hypertrophy of the interventricular myocardial septum, myocardial hypertrophy, and pulmonic stenosis. She had mildly delayed development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21797849" 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>K147 is a conserved amino acid within a motif required for guanine base binding by KRAS. K147 is also ubiquitinated, leading to increased KRAS activation by GEF proteins. Using in vitro assays and transfected COS-7 cells, <a href="#23" class="mim-tip-reference" title="Cirstea, I. C., Gremer, L., Dvorsky, R., Zhang, S.-C., Piekorz, R. P., Zenker, M., Ahmadian, M. R. <strong>Diverging gain-of-function mechanisms of two novel KRAS mutations associated with Noonan and cardio-facio-cutaneous syndromes.</strong> Hum. Molec. Genet. 22: 262-270, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23059812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23059812</a>] [<a href="https://doi.org/10.1093/hmg/dds426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23059812">Cirstea et al. (2013)</a> found that the K147E mutation significantly increased nucleotide dissociation in KRAS, generating a self-activating protein that acted independently of upstream signaling. However, overactivity of K147E mutant KRAS was subject to normal downregulation by RasGAP (see <a href="/entry/139150">139150</a>) and had 2-fold lower affinity for RAF1 kinase (<a href="/entry/164760">164760</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23059812" 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>.0023 RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, 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> rs121913535 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913535;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/rs121913535?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=rs121913535" 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=rs121913535" 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=RCV000038268 OR RCV000144972 OR RCV000681039 OR RCV003335071" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000038268, RCV000144972, RCV000681039, RCV003335071" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000038268...</a>
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<p>In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; <a href="/entry/614470">614470</a>), <a href="#67" class="mim-tip-reference" title="Niemela, J. E., Lu, L., Fleisher, T. A., Davis, J., Caminha, I., Natter, M., Beer, L. A., Dowdell, K. C., Pittaluga, S., Raffeld, M., Rao, V. K., Oliveira, J. B. <strong>Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.</strong> Blood 117: 2883-2886, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21079152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21079152</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21079152[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/10.1182/blood-2010-07-295501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21079152">Niemela et al. (2010)</a> identified a somatic heterozygous c.37G-T transversion in the KRAS gene, resulting in a gly13-to-cys (G13C) substitution. Cells transfected with the mutations showed an increase in active RAS compared to controls, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21079152" 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 OCULOECTODERMAL SYNDROME, 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> rs121913538 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913538;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/rs121913538?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=rs121913538" 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=rs121913538" 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=RCV000201922 OR RCV001839449 OR RCV003654222" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201922, RCV001839449, RCV003654222" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201922...</a>
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<p>In a 25-year-old man with oculoectodermal syndrome (OES; <a href="/entry/600268">600268</a>), who was one of the original boys (patient 2) with OES described by <a href="#97" class="mim-tip-reference" title="Toriello, H. V., Lacassie, Y., Droste, P., Higgins, J. V. <strong>Provisionally unique syndrome of ocular and ectodermal defects in two unrelated boys.</strong> Am. J. Med. Genet. 45: 764-766, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8456858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8456858</a>] [<a href="https://doi.org/10.1002/ajmg.1320450620" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8456858">Toriello et al. (1993)</a>, <a href="#75" class="mim-tip-reference" title="Peacock, J. D., Dykema, K. J., Toriello, H. V., Mooney, M. R., Scholten, D. J., II, Winn, M. E., Borgman, A., Duesbery, N. S., Hiemenga, J. A., Liu, C., Campbell, S., Nickoloff, B. P., Williams, B. O., Steensma, M. <strong>Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations.</strong> Am. J. Med. Genet. 167A: 1429-1435, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25808193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25808193</a>] [<a href="https://doi.org/10.1002/ajmg.a.37048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25808193">Peacock et al. (2015)</a> identified heterozygosity for a somatic c.57G-C transversion (c.57G-C, NM_033360.3) in the KRAS gene, resulting in a leu19-to-phe (L19F) substitution (allelic frequency, 16.9%). The mutation was also found in samples from the patient's skin, bone marrow from proximal femur, and peripheral blood (allelic frequencies, 4.7-10.3%). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25808193+8456858" 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>.0025 ARTERIOVENOUS MALFORMATION OF THE BRAIN, SOMATIC</strong>
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KRAS, GLY12ASP
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013411 OR RCV000022799 OR RCV000029214 OR RCV000029215 OR RCV000144969 OR RCV000144970 OR RCV000150896 OR RCV000150897 OR RCV000272938 OR RCV000433573 OR RCV000548006 OR RCV000585796 OR RCV000662266 OR RCV000856666 OR RCV001799604 OR RCV001839445 OR RCV002508117 OR RCV003327361 OR RCV004018620 OR RCV004554600 OR RCV004668724 OR RCV005007840" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013411, RCV000022799, RCV000029214, RCV000029215, RCV000144969, RCV000144970, RCV000150896, RCV000150897, RCV000272938, RCV000433573, RCV000548006, RCV000585796, RCV000662266, RCV000856666, RCV001799604, RCV001839445, RCV002508117, RCV003327361, RCV004018620, RCV004554600, RCV004668724, RCV005007840" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013411...</a>
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<p>Using exome DNA sequencing and droplet digital PCR analysis, <a href="#70" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29298116[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/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al. (2018)</a> identified a gly12-to-asp (G12D, c.35G-A) mutation in a total of 32 of 72 arteriovenous malformations of the brain (BAVM; <a href="/entry/108010">108010</a>), and in none of 21 paired blood samples. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12V variant (<a href="#0026">190070.0026</a>) were present in 2.4 to 4.0% of the sequence reads per sample. The G12D mutation drove MAPK-ERK activity in endothelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29298116" 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 ARTERIOVENOUS MALFORMATION OF THE BRAIN, SOMATIC</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013413 OR RCV000029216 OR RCV000150895 OR RCV000154262 OR RCV000157944 OR RCV000585801 OR RCV002291496 OR RCV003322589 OR RCV003455987 OR RCV003539760 OR RCV004668725" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013413, RCV000029216, RCV000150895, RCV000154262, RCV000157944, RCV000585801, RCV002291496, RCV003322589, RCV003455987, RCV003539760, RCV004668725" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013413...</a>
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<p>Using exome DNA sequencing and droplet digital PCR analysis, <a href="#70" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29298116[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/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al. (2018)</a> identified a gly12-to-val (G12D, c.35G-T) mutation in a total of 13 of 72 arteriovenous malformations of the brain (BAVM; <a href="/entry/108010">108010</a>), and in none of 21 paired blood samples. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12D variant (<a href="#0025">190070.0025</a>) were present in 2.4 to 4.0% of the sequence reads per sample. The G12V mutation drove MAPK-ERK activity in endothelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29298116" 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">rs121913527 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913527;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=rs121913527" 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=rs121913527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In lesional tissues from a 6-year-old boy with oculoectodermal syndrome (OES; <a href="/entry/600268">600268</a>), originally reported by <a href="#6" class="mim-tip-reference" title="Aslan, D., Akata, R. F., Schroder, J., Happle, R., Moog, U., Bartsch, O. <strong>Oculoectodermal syndrome: report of a new case with a braod clinical spectrum.</strong> Am. J. Med. Genet. 164A: 2947-2951, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25251940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25251940</a>] [<a href="https://doi.org/10.1002/ajmg.a.36727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25251940">Aslan et al. (2014)</a>, <a href="#13" class="mim-tip-reference" title="Boppudi, S., Bogershausen, N., Hove, H. B., Percin, E. F., Aslan, D., Dvorsky, R., Kayhan, G., Li, Y., Cursiefen, C., Tantcheva-Poor, I., Toft, P. B., Bartsch, O., Lissewski, C., Wieland, I., Jakubiczka, S., Wollnik, B., Ahmadian, M. R., Heindl, L. M., Zenker, M. <strong>Specific mosaic KRAS mutations affecting codon 146 cause oculoectodermal syndrome and encephalocraniocutaneous lipomatosis.</strong> Clin. Genet. 90: 334-342, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26970110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26970110</a>] [<a href="https://doi.org/10.1111/cge.12775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26970110">Boppudi et al. (2016)</a> identified somatic mosaicism for a c.436G-A transition (c.436G-A, ENST00000311936) in the KRAS gene, resulting in an ala146-to-thr (A146T) substitution. The mutant allele frequency ranged from 11% to 38% in lesional tissue samples, and was not found in leukocyte DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26970110+25251940" 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 4-year-old Mexican girl with OES (patient 1), <a href="#20" class="mim-tip-reference" title="Chacon-Camacho, O. F., Lopez-Moreno, D., Morales-Sanchez, M. A., Hofmann, E., Pacheco-Quito, M., Wieland, I., Cortes-Gonzalez, V., Villanueva-Mendoza, C., Zenker, M., Zenteno, J. C. <strong>Expansion of the phenotypic spectrum and description of molecular findings in a cohort of patients with oculocutaneous mosaic RASopathies.</strong> Molec. Genet. Genomic Med. 7: e625, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30891959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30891959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30891959[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/mgg3.625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30891959">Chacon-Camacho et al. (2019)</a> identified somatic mosaicism for the A146T mutation in the KRAS gene. The mutant allele frequency was 28% in lesional tissue, and the variant was not detected in DNA isolated from blood leukocytes or buccal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30891959" 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">rs1057519725 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519725;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=rs1057519725" 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=rs1057519725" 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=RCV000791299 OR RCV001839452 OR RCV002524688 OR RCV003332167 OR RCV003488585 OR RCV004760489" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000791299, RCV001839452, RCV002524688, RCV003332167, RCV003488585, RCV004760489" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000791299...</a>
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<p>In 2 unrelated children with oculoectodermal syndrome (OES; <a href="/entry/600268">600268</a>), <a href="#13" class="mim-tip-reference" title="Boppudi, S., Bogershausen, N., Hove, H. B., Percin, E. F., Aslan, D., Dvorsky, R., Kayhan, G., Li, Y., Cursiefen, C., Tantcheva-Poor, I., Toft, P. B., Bartsch, O., Lissewski, C., Wieland, I., Jakubiczka, S., Wollnik, B., Ahmadian, M. R., Heindl, L. M., Zenker, M. <strong>Specific mosaic KRAS mutations affecting codon 146 cause oculoectodermal syndrome and encephalocraniocutaneous lipomatosis.</strong> Clin. Genet. 90: 334-342, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26970110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26970110</a>] [<a href="https://doi.org/10.1111/cge.12775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26970110">Boppudi et al. (2016)</a> identified somatic mosaicism for a c.437C-T transition (c.437C-T, ENST00000311936) in the KRAS gene, resulting in an ala146-to-val (A146V) substitution. The mutant allele frequency ranged from less than 10% to 40% in lesional tissue samples, and was not found in leukocyte DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26970110" 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 12-year-old Mexican boy with OES (patient 2), <a href="#20" class="mim-tip-reference" title="Chacon-Camacho, O. F., Lopez-Moreno, D., Morales-Sanchez, M. A., Hofmann, E., Pacheco-Quito, M., Wieland, I., Cortes-Gonzalez, V., Villanueva-Mendoza, C., Zenker, M., Zenteno, J. C. <strong>Expansion of the phenotypic spectrum and description of molecular findings in a cohort of patients with oculocutaneous mosaic RASopathies.</strong> Molec. Genet. Genomic Med. 7: e625, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30891959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30891959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30891959[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/mgg3.625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30891959">Chacon-Camacho et al. (2019)</a> identified somatic mosaicism for the A146V mutation in the KRAS gene. The mutant allele frequency was 26% to 27% in lesional tissues, and the variant was not detected in DNA isolated from blood leukocytes or buccal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30891959" 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="#Capon1983" class="mim-tip-reference" title="Capon, D. J., Seeburg, P. H., McGrath, J. P., Hayflick, J. S., Edman, U., Levinson, A. D., Goeddel, D. V. <strong>Activation of Ki-ras2 gene in human colon and lung carcinomas by two different point mutations.</strong> Nature 304: 507-513, 1983.">Capon et al. (1983)</a>; <a href="#Der1983" class="mim-tip-reference" title="Der, C. J., Cooper, G. M. <strong>Altered gene products are associated with activation of cellular ras-k genes in human lung and colon carcinomas.</strong> Cell 32: 201-208, 1983.">Der and Cooper (1983)</a>; <a href="#Sakaguchi1984" class="mim-tip-reference" title="Sakaguchi, A. Y., Zabel, B. U., Grzeschik, K. H., Law, M. L., Ellis, R. W., Skolnick, E. M., Naylor, S. L. <strong>Regional localization of two human cellular Kirsten ras genes on chromosomes 6 and 12.</strong> Molec. Cell. Biol. 4: 989-993, 1984.">Sakaguchi et al. (1984)</a>; <a href="#Shimizu1983" class="mim-tip-reference" title="Shimizu, K., Birnbaum, D., Ruley, M. A., Fasano, O., Suard, Y., Edlund, L., Taparowsky, E., Goldfarb, M., Wigler, M. <strong>Structure of the Ki-ras gene of the human lung carcinoma cell line Calu-1.</strong> Nature 304: 497-500, 1983.">Shimizu et al. (1983)</a>
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Ahrendt, S. A., Decker, P. A., Alawi, E. A., Zhu, Y., Sanchez-Cespedes, M., Yang, S. C., Haasler, G. B., Kajdacsy-Balla, A., Demeure, M. J., Sidransky, D.
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<strong>Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung.</strong>
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Cancer 92: 1525-1530, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11745231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11745231</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11745231" 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/10.1002/1097-0142(20010915)92:6<1525::aid-cncr1478>3.0.co;2-h" target="_blank">Full Text</a>]
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<strong>Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.</strong>
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Cell 53: 549-554, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2453289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2453289</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2453289" 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/10.1016/0092-8674(88)90571-5" target="_blank">Full Text</a>]
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Amendola, C. R., Mahaffey, J. P., Parker, S. J., Ahearn, I. M., Chen, W.-C., Zhou, M., Court, H., Shi, J., Mendoza, S. L., Morten, M. J., Rothenberg, E., Gottlieb, E., Wadghiri, Y. Z., Possemato, R., Hubbard, S. R., Balmain, A., Kimmelman, A. C., Philips, M. R.
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<strong>KRAS4A directly regulates hexokinase 1.</strong>
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Nature 576: 482-486, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31827279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31827279</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31827279[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=31827279" 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/s41586-019-1832-9" target="_blank">Full Text</a>]
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Andreyev, H. J. N., Tilsed, J. V. T., Cunningham, D., Sampson, S. A., Norman, A. R., Schneider, H. J., Clarke, P. A.
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<strong>K-ras mutations in patients with early colorectal cancers.</strong>
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[<a href="https://doi.org/10.1038/s41586-019-1062-1" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16857939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16857939</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16857939" 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.1129551" target="_blank">Full Text</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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[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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Yun, J., Rago, C., Cheong, I., Pagliarini, R., Angenendt, P., Rajagopalan, H., Schmidt, K., Willson, J. K. V., Markowitz, S., Zhou, S., Diaz, L. A., Jr., Velculescu, V. E., Lengauer, C., Kinzler, K. W., Vogelstein, B., Papadopoulos, N.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19661383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19661383</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19661383[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=19661383" 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.1174229" target="_blank">Full Text</a>]
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Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17056636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17056636</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17056636" 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/10.1136/jmg.2006.046300" target="_blank">Full Text</a>]
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Zhang, H., Liu, X., Zhang, K., Chen, C.-K., Frederick, J. M., Prestwich, G. D., Baehr, W.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14561760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14561760</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14561760" 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/10.1074/jbc.M306559200" target="_blank">Full Text</a>]
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Zhang, Z., Wang, Y., Vikis, H. G., Johnson, L., Liu, G., Li, J., Anderson, M. W., Sills, R. C., Hong, H. L., Devereux, T. R., Jacks, T., Guan, K.-L., You, M.
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<strong>Wildtype Kras2 can inhibit lung carcinogenesis in mice.</strong>
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Nature Genet. 29: 25-33, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528387</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528387" 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/ng721" target="_blank">Full Text</a>]
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Zimmermann, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S. A., Triola, G., Wittinghofer, A., Bastiaens, P. I. H., Waldmann, H.
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<strong>Small molecule inhibition of the KRAS-PDE-delta interaction impairs oncogenic KRAS signalling.</strong>
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Nature 497: 638-642, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23698361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23698361</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23698361" 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/nature12205" target="_blank">Full Text</a>]
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Sonja A. Rasmussen - updated : 07/25/2022
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Bao Lige - updated : 03/09/2022<br>Ada Hamosh - updated : 05/13/2020<br>Ada Hamosh - updated : 12/10/2019<br>Ada Hamosh - updated : 09/12/2019<br>Marla J. F. O'Neill - updated : 08/01/2019<br>Ada Hamosh - updated : 03/06/2018<br>Ada Hamosh - updated : 09/30/2016<br>Ada Hamosh - updated : 02/17/2016<br>Nara Sobreira - updated : 11/11/2015<br>Cassandra L. Kniffin - updated : 11/12/2014<br>Patricia A. Hartz - updated : 5/23/2014<br>Ada Hamosh - updated : 12/6/2013<br>Ada Hamosh - updated : 7/9/2013<br>Ada Hamosh - updated : 7/8/2013<br>Cassandra L. Kniffin - updated : 1/30/2013<br>Cassandra L. Kniffin - updated : 7/25/2012<br>Ada Hamosh - updated : 7/17/2012<br>Cassandra L. Kniffin - updated : 6/28/2012<br>Marla J. F. O'Neill - updated : 11/29/2011<br>Cassandra L. Kniffin - updated : 2/21/2011<br>Ada Hamosh - updated : 2/3/2011<br>Ada Hamosh - updated : 8/17/2010<br>Ada Hamosh - updated : 3/9/2010<br>Ada Hamosh - updated : 12/29/2009<br>Cassandra L. Kniffin - updated : 10/27/2009<br>Ada Hamosh - updated : 10/13/2009<br>Marla J. F. O'Neill - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 3/3/2009<br>Ada Hamosh - updated : 1/20/2009<br>Ada Hamosh - updated : 7/29/2008<br>Cassandra L. Kniffin - updated : 3/17/2008<br>Ada Hamosh - updated : 11/12/2007<br>George E. Tiller - updated : 4/5/2007<br>Cassandra L. Kniffin - reorganized : 3/8/2007<br>Cassandra L. Kniffin - updated : 3/2/2007<br>Cassandra L. Kniffin - updated : 2/15/2007<br>Ada Hamosh - updated : 2/8/2007<br>Ada Hamosh - updated : 11/28/2006<br>Victor A. McKusick - updated : 6/13/2006<br>Patricia A. Hartz - updated : 4/10/2006<br>Patricia A. Hartz - updated : 3/28/2006<br>Victor A. McKusick - updated : 2/24/2006<br>Ada Hamosh - updated : 9/7/2005<br>Stylianos E. Antonarakis - updated : 3/28/2005<br>Marla J. F. O'Neill - updated : 3/22/2005<br>Victor A. McKusick - updated : 12/16/2003<br>John A. Phillips, III - updated : 9/2/2003<br>John A. Phillips, III - updated : 9/2/2003<br>Ada Hamosh - updated : 9/17/2002<br>Victor A. McKusick - updated : 8/15/2002<br>Victor A. McKusick - updated : 12/13/2001<br>Victor A. McKusick - updated : 9/26/2001<br>Victor A. McKusick - updated : 9/4/2001<br>Victor A. McKusick - updated : 8/24/2001<br>Ada Hamosh - updated : 4/23/2001<br>Ada Hamosh - updated : 4/28/2000<br>Ada Hamosh - updated : 2/11/2000<br>Paul Brennan - updated : 7/31/1998<br>Victor A. McKusick - updated : 3/27/1998<br>Paul Brennan - updated : 11/14/1997<br>Victor A. McKusick - edited : 3/3/1997<br>Mark H. Paalman - edited : 1/10/1997
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Victor A. McKusick : 6/2/1986
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carol : 07/25/2022<br>carol : 05/04/2022<br>carol : 04/19/2022<br>mgross : 03/09/2022<br>carol : 11/04/2021<br>carol : 01/14/2021<br>alopez : 06/22/2020<br>alopez : 05/13/2020<br>alopez : 12/10/2019<br>carol : 10/02/2019<br>alopez : 09/12/2019<br>alopez : 08/01/2019<br>alopez : 08/01/2019<br>carol : 07/24/2019<br>carol : 07/23/2019<br>carol : 03/07/2018<br>alopez : 03/06/2018<br>carol : 08/24/2017<br>alopez : 09/30/2016<br>carol : 09/02/2016<br>alopez : 02/17/2016<br>carol : 11/11/2015<br>alopez : 8/31/2015<br>carol : 11/18/2014<br>mcolton : 11/13/2014<br>ckniffin : 11/12/2014<br>mgross : 5/23/2014<br>mgross : 5/23/2014<br>mcolton : 5/22/2014<br>mcolton : 5/22/2014<br>alopez : 12/6/2013<br>alopez : 7/9/2013<br>alopez : 7/9/2013<br>alopez : 7/8/2013<br>alopez : 6/20/2013<br>alopez : 2/6/2013<br>ckniffin : 1/30/2013<br>carol : 7/26/2012<br>carol : 7/26/2012<br>carol : 7/25/2012<br>ckniffin : 7/25/2012<br>alopez : 7/19/2012<br>terry : 7/17/2012<br>terry : 7/3/2012<br>carol : 7/2/2012<br>ckniffin : 6/28/2012<br>terry : 4/9/2012<br>alopez : 3/7/2012<br>carol : 12/8/2011<br>carol : 11/29/2011<br>terry : 3/10/2011<br>wwang : 3/1/2011<br>ckniffin : 2/21/2011<br>alopez : 2/7/2011<br>alopez : 2/7/2011<br>alopez : 2/7/2011<br>alopez : 2/7/2011<br>terry : 2/3/2011<br>terry : 11/3/2010<br>alopez : 8/20/2010<br>terry : 8/17/2010<br>alopez : 3/9/2010<br>terry : 3/9/2010<br>alopez : 1/6/2010<br>terry : 12/29/2009<br>carol : 11/23/2009<br>carol : 11/23/2009<br>wwang : 11/6/2009<br>ckniffin : 10/27/2009<br>alopez : 10/23/2009<br>terry : 10/13/2009<br>joanna : 9/14/2009<br>wwang : 6/3/2009<br>terry : 6/1/2009<br>wwang : 3/5/2009<br>ckniffin : 3/3/2009<br>alopez : 2/6/2009<br>carol : 2/6/2009<br>terry : 1/20/2009<br>alopez : 7/31/2008<br>terry : 7/29/2008<br>wwang : 3/19/2008<br>ckniffin : 3/17/2008<br>alopez : 11/14/2007<br>alopez : 11/14/2007<br>terry : 11/12/2007<br>carol : 9/10/2007<br>carol : 9/6/2007<br>alopez : 4/13/2007<br>terry : 4/5/2007<br>carol : 3/8/2007<br>carol : 3/8/2007<br>ckniffin : 3/8/2007<br>ckniffin : 3/2/2007<br>wwang : 2/19/2007<br>ckniffin : 2/15/2007<br>alopez : 2/8/2007<br>alopez : 2/8/2007<br>alopez : 2/8/2007<br>terry : 2/1/2007<br>alopez : 12/7/2006<br>terry : 11/28/2006<br>alopez : 6/16/2006<br>terry : 6/13/2006<br>mgross : 4/14/2006<br>terry : 4/10/2006<br>wwang : 3/30/2006<br>terry : 3/28/2006<br>alopez : 3/3/2006<br>terry : 2/24/2006<br>alopez : 9/14/2005<br>terry : 9/7/2005<br>alopez : 7/14/2005<br>carol : 5/27/2005<br>mgross : 3/28/2005<br>tkritzer : 3/22/2005<br>tkritzer : 12/16/2003<br>cwells : 11/6/2003<br>alopez : 9/2/2003<br>alopez : 9/2/2003<br>terry : 1/2/2003<br>terry : 11/22/2002<br>alopez : 9/17/2002<br>tkritzer : 8/21/2002<br>tkritzer : 8/19/2002<br>terry : 8/15/2002<br>terry : 3/5/2002<br>alopez : 2/5/2002<br>alopez : 1/22/2002<br>carol : 1/3/2002<br>mcapotos : 12/19/2001<br>terry : 12/13/2001<br>carol : 10/4/2001<br>mcapotos : 10/3/2001<br>terry : 9/26/2001<br>alopez : 9/4/2001<br>alopez : 8/27/2001<br>terry : 8/24/2001<br>alopez : 4/25/2001<br>terry : 4/23/2001<br>alopez : 5/1/2000<br>terry : 4/28/2000<br>alopez : 2/15/2000<br>terry : 2/11/2000<br>mgross : 6/22/1999<br>alopez : 9/22/1998<br>alopez : 9/22/1998<br>terry : 7/24/1998<br>dkim : 7/23/1998<br>psherman : 3/27/1998<br>dholmes : 3/6/1998<br>alopez : 11/26/1997<br>alopez : 11/26/1997<br>alopez : 11/17/1997<br>alopez : 11/17/1997<br>alopez : 11/17/1997<br>alopez : 11/14/1997<br>mark : 3/3/1997<br>mark : 1/10/1997<br>mark : 1/10/1997<br>terry : 11/6/1996<br>terry : 10/31/1996<br>mark : 8/10/1995<br>mimadm : 6/7/1995<br>carol : 11/1/1993<br>carol : 6/30/1993<br>carol : 6/22/1993<br>carol : 6/7/1993
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="container visible-print-block">
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
<div class="col-md-8 col-md-offset-1">
|
|
|
|
<div>
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 190070
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
KRAS PROTOONCOGENE, GTPase; KRAS
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
V-KI-RAS2 KIRSTEN RAT SARCOMA VIRAL ONCOGENE HOMOLOG<br />
|
|
ONCOGENE KRAS2; KRAS2<br />
|
|
KIRSTEN MURINE SARCOMA VIRUS 2; RASK2<br />
|
|
C-KRAS
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
V-KI-RAS1 PSEUDOGENE, INCLUDED; KRAS1P, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
ONCOGENE KRAS1, INCLUDED; KRAS1, INCLUDED<br />
|
|
KIRSTEN RAS1, INCLUDED; RASK1, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: KRAS</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 12p12.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 12:25,205,246-25,250,929 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="12">
|
|
<span class="mim-font">
|
|
12p12.1
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Arteriovenous malformation of the brain, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
108010
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Bladder cancer, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
109800
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Breast cancer, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114480
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiofaciocutaneous syndrome 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615278
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Gastric cancer, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613659
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukemia, acute myeloid, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
601626
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Lung cancer, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
211980
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Noonan syndrome 3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
609942
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Oculoectodermal syndrome, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
600268
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Pancreatic carcinoma, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
260350
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
RAS-associated autoimmune leukoproliferative disorder
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614470
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
163200
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The KRAS gene encodes the human cellular homolog of a transforming gene isolated from the Kirsten rat sarcoma virus. The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers. The most well-studied members of the RAS (derived from 'RAt Sarcoma' virus) gene family include KRAS, HRAS (190020), and NRAS (164790). These genes encode immunologically related proteins with a molecular mass of 21 kD and are homologs of rodent sarcoma virus genes that have transforming abilities. While these wildtype cellular proteins in humans play a vital role in normal tissue signaling, including proliferation, differentiation, and senescence, mutated genes are potent oncogenes that play a role in many human cancers (Weinberg, 1982; Kranenburg, 2005). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
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<p>Der et al. (1982) identified a new human DNA sequence homologous to the transforming oncogene of the Kirsten (ras-K) murine sarcoma virus within mouse 3T3 fibroblast cells transformed by DNA from an undifferentiated human lung cancer cell line (LX-1). The findings showed that KRAS could act as an oncogene in human cancer. </p><p>Chang et al. (1982) isolated clones corresponding to the human cellular KRAS gene from human placental and embryonic cDNA libraries. Two isoforms were identified, designated KRAS1 and KRAS2. KRAS1 contained 0.9 kb homologous to viral Kras and had 1 intervening sequence, and KRAS2 contained 0.3 kb homologous to viral Kras. McCoy et al. (1983) characterized the KRAS gene isolated from a human colon adenocarcinoma cell line (SW840) and determined that it corresponded to KRAS2 as identified by Chang et al. (1982). The KRAS2 oncogene was amplified in several tumor cell lines. </p><p>McGrath et al. (1983) cloned the KRAS1 and KRAS2 genes and determined that the KRAS1 gene is a pseudogene. The KRAS2 gene encodes a 188-residue protein with a molecular mass of 21.66 kD. It showed only 6 amino acid differences from the viral gene. Comparison of the 2 KRAS genes showed that KRAS1 is lacking several intervening sequences, consistent with it being a pseudogene derived from a processed KRAS2 mRNA. The major KRAS2 mRNA transcript is 5.5 kb. Alternative splicing results in 2 variants, isoforms A and B, that differ in the C-terminal region. </p><p>Alternative splicing of exon 5 results in the KRASA and KRASB isoforms. Exon 6 contains the C-terminal region in KRASB, whereas it encodes the 3-prime untranslated region in KRASA. The differing C-terminal regions of these isoforms are subjected to posttranslational modifications. The differential posttranslational processing has profound functional effects leading to alternative trafficking pathways and protein localization (Carta et al., 2006). </p><p>Tsai et al. (2015) noted that the use of alternative fourth exons generates 2 KRAS variants, KRAS4A and KRAS4B, the produce isoforms with distinct membrane-targeting sequences. Using confocal microscopy, Tsai et al. (2015) showed that GFP-tagged KRAS4A localized exclusively to the plasma membrane (PM) of HEK293 cells. Palmitoylation of cys180 in the hypervariable region of KRAS4A was required for efficient targeting of KRAS4A to the PM, but a second signal could target KRAS4A to the PM in the absence of cys180 palmitoylation. The authors identified a C-terminal polybasic region in KRAS4A with 2 clusters of positively charged residues (PB1 and PB2). They found that both palmitoylation and PB2 were required for efficient targeting of KRAS4A to the PM. RT-PCR analysis showed that KRAS4A was expressed in all human cancer cell lines examined, especially in colorectal carcinoma and melanoma cell lines. </p>
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<strong>Gene Structure</strong>
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<p>McGrath et al. (1983) first reported that the KRAS2 gene spans 38 kb and contains 4 exons. Detailed sequence analysis showed that exon 4 has 2 forms, which the authors designated 4A and 4B. </p><p>The KRAS2 gene has been shown to have a total of 6 exons. Exons 2, 3, and 4 are invariant coding exons, whereas exon 5 undergoes alternative splicing. KRASB results from exon 5 skipping. In KRASA mRNA, exon 6 encodes the 3-prime untranslated region. In KRASB mRNA, exon 6 encodes the C-terminal region (Carta et al., 2006). </p>
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<strong>Mapping</strong>
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<p>By in situ hybridization, Popescu et al. (1985) mapped the KRAS2 gene to chromosome 12p12.1-p11.1. By linkage with RFLPs, O'Connell et al. (1985) confirmed the approximate location of KRAS2 on 12p12.1. </p><p><strong><em>Pseudogene</em></strong></p><p>
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The KRAS1 gene is a KRAS2 pseudogene and has been assigned to chromosome 6 (O'Brien et al., 1983; McBride et al., 1983). By in situ hybridization, Popescu et al. (1985) assigned the KRAS1 gene to 6p12-p11. Because KRAS1 was found to be a pseudogene, its official symbol was changed to KRAS1P. </p>
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<strong>Gene Function</strong>
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<p>Johnson et al. (2005) found that the 3 human RAS genes, HRAS, KRAS, and NRAS, contain multiple let-7 (605386) complementary sites in their 3-prime UTRs that allow let-7 miRNA to regulate their expression. Let-7 expression was lower in lung tumors than in normal lung tissue, whereas expression of the RAS proteins was significantly higher in lung tumors, suggesting a possible mechanism for let-7 in cancer. </p><p>Bivona et al. (2006) found that the subcellular localization and function of Kras in mammalian cells was modulated by Pkc (see 176960). Phosphorylation of Kras by Pkc agonists induced rapid translocation of Kras from the plasma membrane to several intracellular membranes, including the outer mitochondrial membrane, where Kras associated with Bclxl (BCL2L1; 600039). Phosphorylated Kras required Bclxl for induction of apoptosis. </p><p>Yeung et al. (2006) devised genetically encoded probes to assess surface potential in intact cells. These probes revealed marked, localized alterations in the change of the inner surface of the plasma membrane of macrophages during the course of phagocytosis. Hydrolysis of phosphoinositides and displacement of phosphatidylserine accounted for the change in surface potential at the phagosomal cup. Signaling molecules such as KRAS, RAC1 (602048), and c-SRC (190090) that are targeted to the membrane by electrostatic interactions were rapidly released from membrane subdomains where the surface charge was altered by lipid remodeling during phagocytosis. </p><p>Heo et al. (2006) surveyed plasma membrane targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein-conjugated Ras, Rab, Arf, and Rho proteins. Of 48 proteins that were localized to the plasma membrane, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate lipids, Heo et al. (2006) developed a chemical phosphatase activation method to deplete plasma membrane phosphatidylinositol 4,5-bisphosphate. Unexpectedly, proteins with polybasic clusters dissociated from the plasma membrane only when both phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate were depleted, arguing that both lipid second messengers jointly regulate plasma membrane targeting. </p><p>Gazin et al. (2007) performed a genomewide RNA interference (RNAi) screen in KRAS-transformed NIH 3T3 cells and identified 28 genes required for RAS-mediated epigenetic silencing of the proapoptotic FAS gene (TNFRSF6; 134637). At least 9 of these RAS epigenetic silencing effectors (RESEs), including the DNA methyltransferase DNMT1 (126375), were directly associated with specific regions of the FAS promoter in KRAS-transformed NIH 3T3 cells but not in untransformed NIH 3T3 cells. RNAi-mediated knockdown of any of the 28 RESEs resulted in failure to recruit DNMT1 to the FAS promoter, loss of FAS promoter hypermethylation, and derepression of FAS expression. Analysis of 5 other epigenetically repressed genes indicated that RAS directs the silencing of multiple unrelated genes through a largely common pathway. Finally, Gazin et al. (2007) showed that 9 RESEs are required for anchorage-independent growth and tumorigenicity of KRAS-transformed NIH 3T3 cells; these 9 genes had not previously been implicated in transformation by RAS. Gazin et al. (2007) concluded that RAS-mediated epigenetic silencing occurs through a specific, complex pathway involving components that are required for maintenance of a fully transformed phenotype. </p><p>Haigis et al. (2008) used genetically engineered mice to determine whether and how the related oncogenes Kras and Nras (164790) regulate homeostasis and tumorigenesis in the colon. Expression of Kras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek (see 176872)-dependent manner. Nras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc (611731)-mutant colonic tumor, activation of Kras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This Kras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant Kras were hypersensitive to inhibition of Raf (see 164760) but not Mek. Haigis et al. (2008) concluded that their studies demonstrated clear phenotypic differences between mutant Kras and Nras, and suggested that the oncogenic phenotype of mutant Kras might be mediated by noncanonical signaling through Ras effector pathways. </p><p>By studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF (164757) genes, Yun et al. (2009) found that GLUT1 (138140), encoding glucose transporter-1, was 1 of 3 genes consistently upregulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low-glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wildtype KRAS alleles were subjected to a low-glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1, and 4% of these survivors had acquired KRAS mutations not present in their parents. The glycolysis inhibitor 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. Yun et al. (2009) concluded that, taken together, these data suggested that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors. </p><p>Meylan et al. (2009) showed that the NF-kappa-B (see 164011) pathway is required for the development of tumors in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (191170) and expression of oncogenic Kras containing the G12D mutation resulted in NF-kappa-B activation in primary mouse embryonic fibroblasts. Conversely, in lung tumor cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappa-B inhibition. Furthermore, the inhibition of NF-kappa-B signaling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumors in vivo, from the time of tumor initiation or after tumor progression, resulted in significantly reduced tumor development. Meylan et al. (2009) concluded that, together, their results indicated a critical function for NF-kappa-B signaling in lung tumor development and, further, that this requirement depends on p53 status. </p><p>Barbie et al. (2009) used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the noncanonical I-kappa-B kinase TBK1 (604834) was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappa-B antiapoptotic signals involving c-REL (164910) and BCLXL (BCL2L1; 600039) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. Barbie et al. (2009) concluded that TBK1 and NF-kappa-B signaling are essential in KRAS mutant tumors, and establish a general approach for the rational identification of codependent pathways in cancer. </p><p>In Drosophila eye-antennal discs, cooperation between Ras(V12), an oncogenic form of the Ras85D protein, and loss-of-function mutations in the conserved tumor suppressor 'scribble' (607733) gives rise to metastatic tumors that display many characteristics observed in human cancers (summary by Wu et al., 2010). Wu et al. (2010) showed that clones of cells bearing different mutations can cooperate to promote tumor growth and invasion in Drosophila. The authors found that the Ras(V12) and scrib-null mutations can also cause tumors when they affect different adjacent epithelial cells. Wu et al. (2010) showed that this interaction between Ras(V12) and scrib-null clones involves JNK signaling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines (see 604260), a compensatory growth mechanism for tissue homeostasis. The development of Ras(V12) tumors can also be triggered by tissue damage, a stress condition that activates JNK signaling. The authors suggested that similar cooperative mechanisms could have a role in the development of human cancers. </p><p>Correct localization and signaling by farnesylated KRAS is regulated by the prenyl-binding protein PDE-delta (PDED; 602676), which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm (Chandra et al., 2012; Zhang et al., 2004). Zimmermann et al. (2013) reported that interfering with the binding of mammalian PDED to KRAS by means of small molecules provided a novel opportunity to suppress oncogenic RAS signaling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDED interaction that selectively bound to the prenyl-binding pocket of PDED with nanomolar affinity, inhibited oncogenic RAS signaling, and suppressed in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. </p><p>Yun et al. (2015) found that cultured human colorectal cancer cells harboring KRAS or BRAF (164757) 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>Using coexpression analysis, Tsai et al. (2015) showed that, unlike KRAS4B, KRAS4A did not bind PDE6-delta, even though KRAS4A and KRAS4B had identical steady-state localizations at the PM. Further analysis revealed that both membrane-targeting signals of KRAS4A supported its downstream signaling, and that either of the 2 was sufficient for signal output. </p><p>Yao et al. (2019) developed an unbiased functional target discovery platform to query oncogeneic KRAS-dependent changes of the pancreatic ductal adenocarcinoma surfaceome, which revealed syndecan-1 (SDC1; 186355) as a protein that is upregulated at the cell surface by oncogenic KRAS. Localization of SDC1 at the cell surface, where it regulates macropinocytosis, an essential metabolic pathway that fuels pancreatic ductal adenocarcinoma cell growth, is essential for disease maintenance and progression. </p><p>Amendola et al. (2019) reported a direct, GTP-dependent interaction between the KRAS exon 4A-specific isoform KRAS4A and hexokinase-1 (HK1; 142600) that alters the activity of the kinase, and thereby established that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically. </p><p><strong><em>Regulation of KRAS Expression by KRAS1P Transcript Levels</em></strong></p><p>
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Following their finding that PTENP1 (613531), a pseudogene of the PTEN (601728) tumor suppressor gene, can derepress PTEN by acting as a decoy for PTEN-targeting miRNAS, Poliseno et al. (2010) extended their analysis to the oncogene KRAS and its pseudogene KRAS1. KRAS1P 3-prime UTR overexpression in DU145 prostate cancer cells resulted in increased KRAS mRNA abundance and accelerated cell growth. They also found that KRAS and KRAS1P transcript levels were positively correlated in prostate cancer. Notably, the KRAS1P locus 6p12-p11 is amplified in different human tumors, including neuroblastoma, retinoblastoma, and hepatocellular carcinoma. Poliseno et al. (2010) concluded that their findings together pointed to a putative protooncogenic role for KRAS1P, and supported the notion that pseudogene functions mirror the functions of their cognate genes as explained by a miRNA decoy mechanism. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Role in Solid Tumors</em></strong></p><p>
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KRAS is said to be one of the most activated oncogenes, with 17 to 25% of all human tumors harboring an activating KRAS mutation (Kranenburg, 2005). Critical regions of the KRAS gene for oncogenic activation include codons 12, 13, 59, 61, and 63 (Grimmond et al., 1992). These activating mutations cause Ras to accumulate in the active GTP-bound state by impairing intrinsic GTPase activity and conferring resistance to GTPase activating proteins (Zenker et al., 2007). </p><p>In a study of 96 human tumors or tumor cell lines in the NIH 3T3 transforming system, Pulciani et al. (1982) found a mutated HRAS locus only in a single cancer cell line, whereas transforming KRAS genes were identified in 8 different carcinomas and sarcomas. KRAS appeared to be involved in malignancy much more often than HRAS. In a serous cystadenocarcinoma of the ovary (167000), Feig et al. (1984) showed the presence of an activated KRAS oncogene that was not activated in normal cells of the same patient. The transforming gene product displayed an electrophoretic mobility pattern that differed from that of KRAS transforming proteins in other tumors, suggesting a novel somatic KRAS mutation in this tumor. </p><p>In a cell line of human lung cancer (211980), Nakano et al. (1984) identified a mutation in the KRAS2 gene (190070.0001), resulting in gene activation with transforming ability of the mutant protein. </p><p>Rodenhuis et al. (1987) used a novel, highly sensitive assay based on oligonucleotide hybridization following in vitro amplification to examine DNA from 39 lung tumor specimens. The KRAS gene was found to be activated by point mutations in codon 12 in 5 of 10 adenocarcinomas. Two of these tumors were less than 2 cm in size and had not metastasized. No HRAS, KRAS, or NRAS mutations were observed in 15 squamous cell carcinomas, 10 large cell carcinomas, 1 carcinoid tumor, 2 metastatic adenocarcinomas from primary tumors outside the lung, and 1 small cell carcinoma. An approximately 20-fold amplification of the unmutated KRAS gene was observed in a tumor that proved to be a solitary lung metastasis of a rectal carcinoma. </p><p>Yanez et al. (1987) found mutations in codon 12 of the KRAS gene in 4 of 16 colon cancers (114500), 2 of 27 lung cancers, and 1 of 8 breast cancers (114480); no mutations were found at codon position 61. </p><p>The highest observed frequency of KRAS2 point mutations occurs in pancreatic carcinomas (260350), with 90% of the patients having at least 1 KRAS2 mutation (Almoguera et al., 1988; Smit et al., 1988). Most of these mutations are in codon 12 (see, e.g., G12D, 190070.0005 and G12V, 190070.0006) (Hruban et al., 1993). </p><p>Burmer and Loeb (1989) identified KRAS2 mutations in both diploid and aneuploid cells in colon adenomas and carcinomas. Twenty-six of 40 colon carcinomas contained mutations at codon 12, and 9 of the 12 adenomas studied contained similar mutations. </p><p>Sidransky et al. (1992) found that KRAS mutations were detectable in DNA purified from stool in 8 of 9 patients with colorectal tumors that contained KRAS mutations. Takeda et al. (1993) used a mutant-allele-specific amplification (MASA) method to detect KRAS mutations in cells obtained from the sputum of patients with lung cancer. A mutation was found in 1 of 5 patients studied. The authors suggested that the MASA system could be applied to an examination of metastatic lung carcinomas, particularly from adenocarcinomas of the colon and pancreas in which KRAS mutations are frequently detected, and to mass screening for colorectal tumors, using DNA isolated from feces as a template. </p><p>Lee et al. (1995) identified mutations in codon 12 of the KRAS gene in 11 (7.9%) of 140 gastric cancers (613659). Seven cases had a G12S mutation (190070.0007) and 2 had a G12D mutation (190070.0005). Tumors located in the upper third of the stomach had a significantly higher frequency of KRAS codon 12 mutations (3 of 8; 37.5%) compared with tumors located in the middle (4 of 29; 13.8%) or lower (3 of 99; 3%) thirds of the stomach (P = 0.001). Among 8 patients with stomach cancer located in the upper part of the stomach, death occurred in 4 of 5 patients with tumors without KRAS gene mutations, but in none of the 3 patients with KRAS gene-mutated tumors. </p><p>Otori et al. (1997) examined tissue sections from 19 hyperplastic colorectal polyps for mutations in exons 12 and 13 of the KRAS gene. KRAS mutations were detected in 9 (47%) of 19 polyps, suggesting that some hyperplastic colorectal polyps may be true premalignant lesions. </p><p>KRAS activation has been recognized in microdissected foci of pancreatic intraepithelial neoplasia (Cubilla and Fitzgerald, 1976; Hruban et al., 2000; Hruban et al., 2000), the candidate precursor lesion of pancreatic cancer previously known as ductal cell hyperplasia. Laghi et al. (2002) found that KRAS codon 12 was mutated in 34 of 41 (83%) pancreatic cancers and in 11 of 13 (85%) biliary cancers. Multiple distinct KRAS mutations were found in 16 pancreatic cancers and in 8 biliary cancers. Multiple KRAS mutations were more frequent in cancers with detectable pancreatic intraepithelial neoplasia than in those without, and individual precursor lesions of the same neoplastic pancreas harbored distinct mutations. The results indicated that clonally distinct precursor lesions of pancreatic cancer may variably contribute to tumor development. </p><p>Nikiforova et al. (2003) analyzed a series of 88 conventional follicular (188470) and Hurthle cell (607464) thyroid tumors for HRAS, NRAS, or KRAS mutations and PAX8 (167415)-PPARG (601487) rearrangements. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations. </p><p>Rajagopalan et al. (2002) systematically evaluated mutations in the BRAF (164757) and KRAS genes in 330 colorectal tumors. There were 32 mutations in BRAF and 169 mutations in KRAS; no tumor exhibited mutations in both BRAF and KRAS. Rajagopalan et al. (2002) concluded that BRAF and KRAS mutations are equivalent in their tumorigenic effects and are mutated at a similar phase of tumorigenesis, after initiation but before malignant conversion. Kim et al. (2003) found 7 KRAS missense mutations in 66 gastric cancers and 16 gastric cancer cell lines. No BRAF mutations were found. </p><p>Oliveira et al. (2004) investigated KRAS in 158 hereditary nonpolyposis colorectal cancer (HNPCC2; 609310) tumors from patients with germline MLH1 (120436), MSH2 (609309) or MSH6 (600678) mutations, 166 microsatellite-unstable (MSI-H), and 688 microsatellite-stable (MSS) sporadic carcinomas. All tumors were characterized for MSI and 81 of 166 sporadic MSI-H colorectal cancers were analyzed for MLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumors, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in MSH2, 32% (29/91) in MLH1, and 83% (5/6) in MSH6 (P = 0.01). KRAS mutation frequency was different between HNPCC, MSS, and MSI-H colorectal cancers (P = 0.002), and MSI-H with MLH1 hypermethylation (P = 0.005). Furthermore, HNPCC colorectal cancers had more G13D (190070.0003) mutations than MSS (P less than 0.0001), MSI-H (P = 0.02) or MSI-H tumors with MLH1 hypermethylation (P = 0.03). HNPCC colorectal and sporadic MSI-H tumors without MLH1 hypermethylation shared similar KRAS mutation frequency, in particular G13D. The authors concluded that depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the MLH1 status) and MSS colorectal cancers may target distinct kinases within the RAS/RAF/MAPK pathway. </p><p>Sommerer et al. (2005) analyzed the KRAS gene in 30 seminomas and 32 nonseminomatous GCTs (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma. KRAS mutations, all involving codon 12, were identified in 2 (7%) of 30 seminomas and 3 (9%) of 32 nonseminomas. </p><p>Groesser et al. (2012) identified somatic mutations in the KRAS gene (G12D, 190070.0005 and G12V, 190070.0006) in 3 (5%) of 65 nevus sebaceous tumors (see 162900). The G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200). The authors postulated that the mosaic mutation likely extends to extracutaneous tissues in the latter disorder, which could explain the phenotypic pleiotropy. </p><p>Vermeulen et al. (2013) quantified the competitive advantage in tumor development of Apc (611731) loss, Kras activation, and p53 (191170) mutations in the mouse intestine. Their findings indicated that the fate conferred by these mutations is not deterministic, and many mutated stem cells are replaced by wildtype stem cells after biased but still stochastic events. Furthermore, Vermeulen et al. (2013) found that p53 mutations display a condition-dependent advantage, and especially in colitis-affected intestines, clones harboring mutations in this gene were favored. Vermeulen et al. (2013) concluded that their work confirmed the notion that the tissue architecture of the intestine suppresses the accumulation of mutated lineages. </p><p><strong><em>Hematologic Malignancies</em></strong></p><p>
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The myelodysplastic syndrome is a preleukemic hematologic disorder characterized by low blood counts, bone marrow cells of abnormal appearance, and progression to acute leukemia in as many as 30% of patients. Liu et al. (1987) identified a transforming allele in the KRAS gene in 2 of 4 patients with preleukemia and in 1 who progressed to acute leukemia from myelodysplastic syndrome. In 1 preleukemic patient, they detected a novel mutation in codon 13 of KRAS in bone marrow cells harvested 1.5 years before the acute leukemia developed. The findings provided evidence that RAS mutations may be involved in the early stages of human leukemia. </p><p>In the bone marrow of a 4-year-old child with acute myeloid leukemia (AML; 601626), Bollag et al. (1996) identified a somatic in-frame 3-bp insertion in the KRAS gene (190070.0008). </p><p>Bezieau et al. (2001) used ARMS (allele-specific amplification method) to evaluate the incidence of NRAS- and KRAS2-activating mutations in patients with multiple myeloma (254500) and related disorders. Mutations were more frequent in KRAS2 than in NRAS. The authors concluded that early mutations in these 2 oncogenes may play a major role in the oncogenesis of multiple myeloma and primary plasma cell leukemia. </p><p>In white blood cells derived from 3 unrelated girls with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified 3 different somatic heterozygous mutations in the KRAS gene (G13D, 190070.0003; G12D, 190070.0005; and G12S, 190070.0007). The patients were ascertained from a cohort of 80 children with JMML. </p><p>The Cancer Genome Atlas Research Network (2013) analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. The Cancer Genome Atlas Research Network (2013) identified recurrent mutations in the NRAS (164790) or KRAS genes in 23/200 (12%) samples. </p><p><strong><em>RAS-Associated Autoimmune Leukoproliferative Disorder</em></strong></p><p>
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In 2 unrelated girls with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified different somatic heterozygous gain-of-function mutations in the KRAS gene (G12D, 190070.0005 and G13C, 190070.0023). The patients presented in early childhood with lymphadenopathy, splenomegaly, and autoimmune disorders. One patient had recurrent infections. In vitro studies indicated that the activating KRAS mutations impaired cytokine withdrawal-induced T-cell apoptosis through suppression of the proapoptotic protein BIM (BCL2L11; 603827) and facilitated lymphocyte proliferation through downregulation of CDKN1B (600778). </p><p><strong><em>Cardiofaciocutaneous Syndrome, Noonan Syndrome 3, and Costello Syndrome</em></strong></p><p>
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Cardiofaciocutaneous (CFC) syndrome (see 115150) is characterized by distinctive facial appearance, heart defects, and mental retardation. CFC shows phenotypic overlap with Noonan syndrome (see 163950) and Costello syndrome (218040). Approximately 40% of individuals with clinically diagnosed Noonan syndrome have gain-of-function mutations in protein-tyrosine phosphatase SHP2 (PTPN11; 176876). Aoki et al. (2005) identified mutations in the HRAS gene in 12 of 13 individuals with Costello syndrome, suggesting that the activation of the RAS-MAPK pathway is the common underlying mechanism of Noonan syndrome, Costello syndrome, and possibly CFC syndrome. In 2 of 43 unrelated individuals with CFC syndrome (CFC2; 615278), Niihori et al. (2006) identified different heterozygous KRAS mutations (G60R, 190070.0009 and D153V, 190070.0010). Neither mutation had previously been identified in individuals with cancer. In the same study, Niihori et al. (2006) found 8 different mutations in the BRAF gene (164757), an isoform in the RAF protooncogene family, in 16 of 40 individuals with CFC syndrome. </p><p>Schubbert et al. (2006) identified 3 de novo germline KRAS mutations (190070.0010-190070.0012) in 5 individuals with Noonan syndrome-3 (NS3; 609942). </p><p>In 2 individuals exhibiting a severe Noonan syndrome-3 phenotype with features overlapping those of CFC and Costello syndromes, Carta et al. (2006) identified 2 different heterozygous KRAS mutations (190070.0014 and 190070.0015). Both mutations were de novo and affected exon 6, which encodes the C-terminal portion of KRAS isoform B but does not contribute to KRAS isoform A. Structural analysis indicated that both substitutions perturb the conformation of the guanine ring-binding pocket of the protein, predicting an increase in the guanine diphosphate/guanine triphosphate (GTP) dissociation rate that would favor GTP binding to the KRASB isoform and bypass the requirement for a guanine nucleotide exchange factor. </p><p>Zenker et al. (2007) identified 11 different germline mutations in the KRAS gene, including 8 novel mutations, in a total of 12 patients with a clinical diagnosis of CFC (2), Noonan syndrome-3 (7), CFC/Noonan syndrome overlap (1), or Costello syndrome (2). All patients showed mild to moderate mental retardation. The 2 unrelated infants with Costello syndrome had 2 different heterozygous mutations (190070.0017-190070.0018). Both patients had coarse facies, loose and redundant skin with deep palmar creases, heart defects, failure to thrive, and moderate mental retardation. Zenker et al. (2007) noted that these patients may later develop features of CFC syndrome, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these diverse but phenotypically related disorders. </p><p>In a 20-year-old woman with clinical features typical of Costello syndrome and additional findings seen in Noonan syndrome, who was negative for mutations in the PTPN11 and HRAS genes, Bertola et al. (2007) identified a mutation in the KRAS gene (K5E; 190070.0019). The authors noted that this mutation was in the same codon as that of 1 of the patients reported by Zenker et al. (2007) (K5N; 190070.0017). </p><p>Schulz et al. (2008) identified mutations in the KRAS gene in 3 (5.9%) of 51 CFC patients. </p><p><strong><em>Development of Resistance to Chemotherapeutic Agents</em></strong></p><p>
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Misale et al. (2012) showed that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR (131550) treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. Misale et al. (2012) concluded that their results identified KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicated that the emergence of KRAS mutant clones can be detected noninvasively months before radiographic progression, and suggested early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. </p><p>Diaz et al. (2012) determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. They found that 9 out of 24 (38%) patients whose tumors were initially KRAS wildtype developed detectable mutations in KRAS in their sera, 3 of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modeling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. Diaz et al. (2012) suggested that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a noninvasive manner. The results also explained why solid tumors develop resistance to targeted therapies in a highly reproducible fashion. </p><p><strong><em>Arteriovenous Malformations of the Brain</em></strong></p><p>
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Nikolaev et al. (2018) analyzed tissue and blood samples from patients with arteriovenous malformations of the brain (BAVM; 108010) to detect somatic mutations. They performed exome DNA sequencing of BAVM tissue samples from 26 patients in the main study group and of paired blood samples from 17 of these patients, and then confirmed their findings using droplet digital PCR analysis of tissue samples from 39 patients in the initial study group (21 of whom had matching blood samples) and from 33 patients in an independent validation group. Nikolaev et al. (2018) detected somatic activating KRAS mutations gly12 to asp (G12D; 190070.0025) and gly12 to val (G12V; 190070.0026) in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from BAVM, Nikolaev et al. (2018) detected KRAS mutations and observed that expression of mutant KRAS (KRAS G12V) in endothelial cells in vitro induced increased ERK activity, increased expression of genes related to angiogenesis and Notch (190198) signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK-ERK signaling (see 176872). Nikolaev et al. (2018) concluded that they identified activating KRAS mutations in the majority of BAVM tissue samples that were analyzed, and proposed that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain epithelial cells. </p><p><strong><em>Oculoectodermal Syndrome</em></strong></p><p>
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In affected tissue from 2 patients with oculoectodermal syndrome (OES; 600268), Peacock et al. (2015) identified somatic mosaicism for 2 different missense mutations in the KRAS gene, G12D (190070.0003) and L19F (190070.0024). </p><p>In 3 unrelated children with OES, Boppudi et al. (2016) identified somatic missense mutations in the KRAS gene, A146T (190070.0027) and A146V (190070.0028), that were mosaic in lesional tissue and absent from leukocyte DNA. </p><p>In a 4-year-old Mexican girl (patient 1) and an unrelated 12-year-old Mexican boy (patient 2) with OES, Chacon-Camacho et al. (2019) identified somatic mosaicism for the previously reported KRAS variants, A146T and A146V, respectively. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between postzygotic somatic mutation in the KRAS gene and melorheostosis, see 166700.</p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Andreyev et al. (1997) used PCR amplification and DNA sequencing to investigate KRAS exon 1 mutations (codons 12 and 13) in histologic sections of colorectal adenocarcinomas. They examined samples from 98 patients with Dukes stage A or B fully resected colorectal cancers. Fourteen of these patients had subsequently relapsed. The presence of a KRAS mutation was not associated with tumor stage or histologic grade; neither was there any association with those patients who relapsed. The authors concluded that detection of KRAS mutation in early colorectal adenocarcinomas was of no prognostic value. </p><p>Porta et al. (1999) found that serum concentrations of organochlorine compounds were significantly higher in patients with exocrine pancreatic cancer with a codon 12 KRAS2 mutation compared to cases without a mutation, with an odds ratio of 8.7 for one organochlorine and 5.3 for another organochlorine. These estimates held after adjusting for total lipids, other covariates, and total polychlorinated biphenyls (PCBs). A specific association was observed between the G12V (190070.0006) mutation and both organochlorine concentrations, with an odds ratio of 15.9 and 24.1 for each of the compounds. A similar pattern was shown for the major diorthochlorinated PCBs. </p><p>Vasko et al. (2003) performed a pooled analysis of 269 mutations in HRAS, KRAS, and NRAS garnered from 39 previous studies of thyroid tumors. Mutations in codon 61 of NRAS were significantly more frequent in follicular tumors (19%) than in papillary tumors (see 188550) (5%) and significantly more frequent in malignant (25%) than in benign (14%) tumors. HRAS mutations in codons 12/13 were found in 2 to 3% of all types of tumors, but HRAS mutations in codon 61 were observed in only 1.4% of tumors, and almost all of them were malignant. KRAS mutations in exon 1 were found more often in papillary than follicular cancers (2.7% vs 1.6%) and were sometimes correlated with special epidemiologic circumstances. The second part of the study by Vasko et al. (2003) involved analysis of 80 follicular tumors from patients living in Marseille (France) and Kiev (Ukraine). HRAS mutations in codons 12/13 were found in 12.5% of common adenomas and in 1 follicular carcinoma (2.9%). Mutations in codon 61 of NRAS occurred in 23.3% and 17.6% of atypical adenomas and follicular carcinomas, respectively. </p>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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<p>Although several studies confirmed that approximately 40% of primary colorectal adenocarcinomas in humans contain a mutated form of the KRAS2 gene, the patterns of mutation at codons 12, 13, and 61 are not the same in different populations. Hayashi et al. (1996) used the MASA method to analyze the frequency and type of point mutations in these 3 codons in 319 colorectal cancer tissues collected from patients in Japan. They then compared these results with those from other sources to examine whether different geographic locations and environmental influences might impose distinct patterns on the spectrum of KRAS mutations. Comparing findings in the U.S., France, and Yugoslavia with those in Japan, a number of significant differences were found. A possible explanation put forth by Hayashi et al. (1996) was that an environmental carcinogen prevailing in a geographic region combines with the susceptibility of a particular tissue to dictate which type of DNA lesion will predominate. The predominance of G-to-A mutations among American and Japanese colorectal cancer patients could be attributable to alkylating agents or to the absence of direct interaction with any carcinogens. The prevalence of G-to-T mutations among Yugoslav and French patients might be ascribed to polycyclic aromatic hydrocarbons and heterocyclic amines. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</h4>
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<span class="mim-text-font">
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<p>Muller et al. (1983) found transcription of KRAS and the McDonough strain of feline sarcoma virus (FMS) gene (see 164770) during mouse development. Furthermore, the differences in transcription in different tissues suggested a specific role for each: FMS was expressed in extraembryonic structures or in transport in these tissues, whereas KRAS was expressed ubiquitously. </p><p>Holland et al. (2000) transferred, in a tissue-specific manner, genes encoding activated forms of Ras and Akt (164730) to astrocytes and neural progenitors in mice. Although neither activated Ras nor Akt alone was sufficient to induce glioblastoma multiforme (GBM; 137800) formation, the combination of activated Ras and Akt induced high-grade gliomas with the histologic features of human GBMs. These tumors appeared to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs, and Holland et al. (2000) demonstrated that AKT activity is increased in most of these tumors, implying that combined activation of these 2 pathways accurately models the biology of this disease. </p><p>Johnson et al. (2001) used a variation of 'hit-and-run' gene targeting to create mouse strains carrying oncogenic alleles of Kras capable of activation only on a spontaneous recombination event in the whole animal. They demonstrated that mice carrying these mutations were highly predisposed to a range of tumor types, predominantly early-onset lung cancer. This model was further characterized by examining the effects of germline mutations in the p53 gene (191170), which is known to be mutated along with KRAS in human tumors. Johnson et al. (2001) concluded that their approach had several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers. </p><p>Zhang et al. (2001) presented evidence of a tumor suppressor role of wildtype KRAS2 in lung tumorigenesis. They found that heterozygous Kras2-deficient mice were highly susceptible to the chemical induction of lung tumors compared to wildtype mice. Activating Kras2 mutations were detected in all chemically induced lung tumors obtained from both wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhibited colony formation and tumor development by transformed NIH/3T3 cells. Allelic loss of wildtype Kras2 was found in 67 to 100% of chemically induced mouse lung adenocarcinomas that harbored a mutant Kras2 allele. These and other data strongly suggested that wildtype Kras2 has tumor suppressor activity and is frequently lost during lung tumor progression. Pfeifer (2001) commented on these findings as representing 'a new verdict for an old convict.' He quoted evidence that the HRAS1 gene may also function as a tumor suppressor. Pfeifer (2001) noted an interesting parallel to the p53 tumor suppressor, which was initially described as an oncogene, carrying point mutations in tumors. Later it was discovered that it is, in fact, the wildtype copy of the gene that functions as a tumor suppressor gene and is capable of reducing cell proliferation. </p><p>Costa et al. (2002) crossed Nf1 (613113) heterozygote mice with mice heterozygous for a null mutation in the Kras gene. Double heterozygotes with decreased Ras function had improved learning relative to Nf1 heterozygote mice. Costa et al. (2002) also showed that the Nf1 +/- mice have increased GABA-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Costa et al. (2002) concluded that learning deficits associated with Nf1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. </p><p>An S17N substitution in any of the RAS proteins produces dominant-inhibitory proteins with higher affinities for exchange factors than normal RAS. These mutants cannot interact with downstream effectors and therefore form unproductive complexes, preventing activation of endogenous RAS. Using experiments in COS-7 cells, mouse fibroblasts, and canine kidney cells, Matallanas et al. (2003) found that the Hras, Kras, and Nras S17N mutants exhibited distinct inhibitory effects that appeared to be due largely to their specific membrane localizations. The authors demonstrated that Hras is present in caveolae, lipid rafts, and bulk disordered membranes, whereas Kras and Nras are present primarily in disordered membranes and lipid rafts, respectively. Thus, the Hras S17N mutant inhibited activation of all 3 wildtype RAS isoforms, the Kras S17N mutant inhibited wildtype Kras and the portion of Hras in disordered membranes, and the Nras S17N mutant inhibited wildtype Nras and the portion of Hras in lipid rafts. </p><p>By delivering a recombinant adenoviral vector expressing Cre recombinase to the bursal cavity that encloses the ovary, Dinulescu et al. (2005) expressed an oncogenic Kras allele within the ovarian surface epithelium and observed benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma (167000); 7 of 15 mice (47%) also developed peritoneal endometriosis (131200). When the Kras mutation was combined with conditional deletion of Pten (601728), all mice developed invasive endometrioid ovarian adenocarcinomas. Dinulescu et al. (2005) stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary. </p><p>Collado et al. (2005) used a mouse model for cancer initiation in humans: the animals had a conditional oncogenic K-rasV12 (190070.0006) allele that is activated only by the enzyme Cre recombinase, causing them to develop multiple lung adenomas (premalignant tumors) and a few lung adenocarcinomas (malignant tumors). Senescence markers previously identified in cultured cells were used to detect oncogene-induced senescence in lung sections from control mice (expressing Cre) and from K-rasV12-expressing mice (expressing Cre and activated K-rasV12). Collado et al. (2005) analyzed p16(INK4a) (600160), an effector of in vitro oncogene-induced senescence, and de novo markers that were identified by using DNA microarray analysis of in vitro oncogene-induced senescence. These de novo markers are p15(INK4b), also known as CDKN2B (600431), DEC1 (BHLHB2; 604256), and DCR2 (TNFRSF10D; 603614). Staining with antibodies against p16(INK4a), p15(INK4b), DEC1, and DCR2 revealed abundant positive cells in adenomas, whereas adenocarcinomas were essentially negative. By contrast, the proliferation marker Ki-67 revealed a weak proliferative index in adenomas compared with adenocarcinomas. Collado et al. (2005) concluded that oncogene-induced senescence may help to restrict tumor progression. They concluded that a substantial number of cells in premalignant tumors undergo oncogene-induced senescence, but that cells in malignant tumors are unable to do this owing to the loss of oncogene-induced senescence effectors such as p16(INK4a) or p53. </p><p>Using an Hras (190020) knockin mouse model, To et al. (2008) demonstrated that specificity for Kras mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target Ras genes. Although the Kras 4A isoform is dispensable for mouse development, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wildtype Kras on the mutant allele. Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The 2 Kras isoforms undergo different posttranslational modifications. To et al. (2008) concluded that their findings may have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers. </p><p>Junttila et al. (2010) modeled the probable therapeutic impact of p53 (191170) restoration in a spontaneously evolving mouse model of nonsmall cell lung cancer (NSCLC) initiated by sporadic oncogenic activation of endogenous KRAS developed by Jackson et al. (2001). Surprisingly, p53 restoration failed to induce significant regression of established tumors, although it did result in a significant decrease in the relative proportion of high-grade tumors. This was due to selective activation of p53 only in the more aggressive tumor cells within each tumor. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signaling sensor p19(ARF) (600160). Junttila et al. (2010) concluded that p53-mediated tumor suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumor evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers. </p><p>A single endogenous mutant Kras allele is sufficient to promote lung tumor formation in mice, but malignant progression requires additional genetic alterations. Junttila et al. (2010) showed that advanced lung tumors from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) (see 190070.0005) allelic enrichment (Kras(G12D)/Kras(wildtype) greater than 1), implying that mutant Kras copy gains are positively selected during progression. Through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, Kerr et al. (2016) demonstrated that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channeling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous nonsmall cell lung cancer cells and in vivo, and in spontaneous advanced murine lung tumors (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumors (Kras(G12D) heterozygous). Finally, Kerr et al. (2016) demonstrated that mutant Kras copy gain creates unique metabolic dependencies that can be exploited to selectively target these aggressive mutant Kras tumors. The authors concluded that mutant Kras lung tumors are not a single disease but rather a heterogeneous group comprising 2 classes of tumors with distinct metabolic profiles, prognosis, and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. </p>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>28 Selected Examples):</strong>
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</span>
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</h4>
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<h4>
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<span class="mim-font">
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<strong>.0001 LUNG CANCER, SOMATIC</strong>
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</span>
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</h4>
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KRAS, GLY12CYS
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<br />
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SNP: rs121913530,
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gnomAD: rs121913530,
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ClinVar: RCV000013406, RCV000038265, RCV000119791, RCV000431049, RCV001292543, RCV001355787, RCV003654176, RCV003996092, RCV004668721
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<p>In a cell line of human lung cancer (211980), Nakano et al. (1984) identified a 34G-T transversion in exon 1 of the KRAS2 gene, resulting in a gly12-to-cys (G12C) substitution. Studies of the mutant protein showed that it had transforming abilities consistent with activation of the gene. </p><p>In a study of 106 prospectively enrolled patients with primary adenocarcinoma of the lung, Ahrendt et al. (2001) found that 92 (87%) were smokers. KRAS2 mutations were detected in 40 of 106 tumors (38%) and were significantly more common in smokers compared with nonsmokers (43% vs 0%; P = 0.001). Thirty-nine of the 40 tumors with KRAS2 mutations had 1 of 4 changes in codon 12, the most common being G12C, which was present in 25 tumors. </p><p><strong><em>Inhibitor of KRAS(G12C)</em></strong></p><p>
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Canon et al. (2019) optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity to knockdown KRAS carrying the G12C variant. Canon et al. (2019) discovered the KRAS(G12C) inhibitor AMG-510 and presented data on its preclinical activity. Treatment with AMG-510 led to the regression of KRAS(G12C) tumors and improved the antitumor efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG-510 resulted in a proinflammatory tumor microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS(G12D) tumors, which suggested adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG-510 demonstrated antitumor activity in the first dosing cohorts and represented a potentially transformative therapy for patients for whom effective treatments are lacking. </p><p>Janne et al. (2022) conducted a phase 2 cohort study to evaluate the clinical efficacy of oral adagrasib, a selective covalent KRAS(G12C) inhibitor, among patients with KRAS(G12C)-mutated nonsmall cell lung cancer who were previously treated with platinum-based chemotherapy and antiprogrammed death 1 or programmed ligand 1 therapy. Among the 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response by blinded independent review. The median duration of response was 8.5 months, with a median progression-free survival of 6.5 months and median overall survival of 12.6 months at last follow-up. Treatment-related adverse events of grade 3 or higher occurred in 44.8%, resulting in a treatment discontinuation rate of 6.9%. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 LUNG CANCER, SQUAMOUS CELL, SOMATIC</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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BLADDER CANCER, SOMATIC, INCLUDED
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</span>
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</div>
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<span class="mim-text-font">
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KRAS, GLY12ARG
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<br />
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SNP: rs121913530,
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gnomAD: rs121913530,
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ClinVar: RCV000013407, RCV000013408, RCV000154401, RCV001356365, RCV002513010, RCV004668722, RCV004813033
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<span class="mim-text-font">
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<p>In a squamous cell lung carcinoma (211980) from a 66-year-old man, Santos et al. (1984) identified a G-to-C transversion in exon 1 of the KRAS2 gene, resulting in a gly12-to-arg (G12R) substitution. The mutation was not identified in the patient's normal bronchial and pulmonary parenchymal tissues or blood lymphocytes. This mutation had previously been identified in a bladder cancer (109800) and a lung cancer. </p>
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<h4>
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<span class="mim-font">
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<strong>.0003 BREAST ADENOCARCINOMA, SOMATIC</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED<br />
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RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC, INCLUDED<br />
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OCULOECTODERMAL SYNDROME, SOMATIC, INCLUDED
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</span>
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</div>
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<span class="mim-text-font">
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KRAS, GLY13ASP
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<br />
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SNP: rs112445441,
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gnomAD: rs112445441,
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ClinVar: RCV000013409, RCV000038269, RCV000144967, RCV000144968, RCV000791297, RCV001092389, RCV001266168, RCV001526657, RCV001813183, RCV001839444, RCV001857340, RCV004549358, RCV004668723, RCV004813034
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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>Breast Adenocarcinoma, Somatic</em></strong></p><p>
|
|
In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 of the KRAS2 gene, resulting in a gly13-to-asp (G13D) substitution and activation of the protein. </p><p><strong><em>Juvenile Myelomonocytic Leukemia, Somatic</em></strong></p><p>
|
|
In white blood cells derived from a 7-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G13D mutation in the KRAS gene. </p><p><strong><em>RAS-associated Autoimmune Leukoproliferative Disorder, Somatic</em></strong></p><p>
|
|
In 2 unrelated children with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Takagi et al. (2011) identified a somatic heterozygous G13D mutation in the KRAS gene. The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. Takagi et al. (2011) noted that the same somatic mutation had been found in patients with JMML, and they postulated that the variable clinical and hematologic features of the 2 disorders may be related to the stage of differentiation at which the KRAS mutation is acquired. </p><p><strong><em>Oculoectodermal Syndrome</em></strong></p><p>
|
|
In a patient (patient 1) with oculoectodermal syndrome (OES; 600268), Peacock et al. (2015) performed whole-genome shotgun sequencing to compare DNA from the patient's femur nonossifying fibroma (NOF) with DNA from her peripheral blood, and identified the G13D mutation (c.38G-A, NM_033360.3) in the KRAS gene. The mutation was confirmed by both Sanger and next-generation sequencing (allelic frequency, 32.9%). The mutation was also detectable in her hyperpigmented skin, periosteum, muscle, and humerus NOF samples (allelic frequencies, 10.3-38.8%), but not in her bone marrow or peripheral blood. </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>.0004 BLADDER CANCER, TRANSITIONAL CELL, 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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KRAS, ALA59THR
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<br />
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SNP: rs121913528,
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ClinVar: RCV000013410
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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 human transitional cell bladder carcinoma cell line (109800), Grimmond et al. (1992) identified a heterozygous G-to-A transition in the KRAS2 gene, resulting in an ala59-to-thr (A59T) substitution. The mutation was present in paraffin-embedded tissue from the primary tumor of the patient. </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 PANCREATIC CARCINOMA, 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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GASTRIC CANCER, SOMATIC, INCLUDED<br />
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EPIDERMAL NEVUS, SOMATIC, INCLUDED<br />
|
|
NEVUS SEBACEOUS, SOMATIC, INCLUDED<br />
|
|
SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC, INCLUDED<br />
|
|
JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED<br />
|
|
RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC, INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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KRAS, GLY12ASP
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<br />
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SNP: rs121913529,
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|
|
gnomAD: rs121913529,
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ClinVar: RCV000013411, RCV000022799, RCV000029214, RCV000029215, RCV000144969, RCV000144970, RCV000150896, RCV000150897, RCV000272938, RCV000433573, RCV000548006, RCV000585796, RCV000662266, RCV000856666, RCV001799604, RCV001839445, RCV002508117, RCV003327361, RCV004018620, RCV004554600, RCV004668724, RCV005007840
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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>Pancreatic Carcinoma, Somatic</em></strong></p><p>
|
|
Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively. </p><p><strong><em>Gastric Cancer, Somatic</em></strong></p><p>
|
|
Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D. </p><p><strong><em>Epidermal Nevus, Somatic</em></strong></p><p>
|
|
Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. </p><p>Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi. </p><p><strong><em>Nevus Sebaceous, Somatic</em></strong></p><p>
|
|
Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017). </p><p><strong><em>Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic</em></strong></p><p>
|
|
The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy. </p><p><strong><em>Juvenile Myelomonocytic Leukemia, Somatic</em></strong></p><p>
|
|
In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene. </p><p><strong><em>RAS-associated Autoimmune Leukoproliferative Disorder, Somatic</em></strong></p><p>
|
|
In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PANCREATIC CARCINOMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEVUS SEBACEOUS, SOMATIC, INCLUDED
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, GLY12VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913529,
|
|
|
|
|
|
gnomAD: rs121913529,
|
|
|
|
|
|
ClinVar: RCV000013413, RCV000029216, RCV000150895, RCV000154262, RCV000157944, RCV000585801, RCV002291496, RCV003322589, RCV003455987, RCV003539760, RCV004668725
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Pancreatic Carcinoma, Somatic</em></strong></p><p>
|
|
For discussion of the gly12-to-val (G12V) substitution that was found in 1 of 53 pancreatic carcinomas (260350) by Motojima et al. (1993), see 190070.0005. </p><p><strong><em>Nevus Sebaceous, Somatic</em></strong></p><p>
|
|
Groesser et al. (2012) identified a somatic G12V mutation in 1 (2%) of 65 nevus sebaceous tumors (see 162900). The tumor also carried a somatic mutation in the HRAS gene (G13R; 190020.0017). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 GASTRIC CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, GLY12SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913530,
|
|
|
|
|
|
gnomAD: rs121913530,
|
|
|
|
|
|
ClinVar: RCV000013414, RCV000038264, RCV000119790, RCV000144971, RCV000782191, RCV001851824, RCV004562205, RCV004668726, RCV004795403
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Gastric Cancer, Somatic</em></strong></p><p>
|
|
Lee et al. (1995) found mutations in codon 12 of the KRAS2 gene in 9 of 140 cases of gastric cancer (613659); 7 cases had a G-to-A transition, resulting in a gly12-to-ser (G12S) substitution. </p><p><strong><em>Juvenile Myelomonocytic Leukemia, Somatic</em></strong></p><p>
|
|
In white blood cells derived from a 4-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12S mutation in the KRAS gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LEUKEMIA, ACUTE MYELOGENOUS, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, 3-BP INS, GLY11INS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs606231202,
|
|
|
|
|
|
|
|
ClinVar: RCV000013415
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the bone marrow of a 4-year-old child with acute myeloid leukemia (AML; 601626), Bollag et al. (1996) identified an in-frame 3-bp insertion in exon 1 of the KRAS2 gene, resulting in an insertion of gly11. Expression of the mutant protein in NIH 3T3 cells caused cellular transformation, and expression in COS cells activated the RAS-mitogen-activated protein kinase signaling pathway. RAS-GTP levels measured in COS cells established that this novel mutant accumulates up to 90% in the GTP state, considerably higher than a residue 12 mutant. This mutation was the first dominant RAS mutation found in human cancer that did not involve residues 12, 13, or 61. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CARDIOFACIOCUTANEOUS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, GLY60ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894359,
|
|
|
|
|
|
|
|
ClinVar: RCV000013416, RCV000157935, RCV000254661, RCV000521390, RCV000844635, RCV001267316, RCV003313917
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an individual with cardiofaciocutaneous syndrome (CFC2; 615278), Niihori et al. (2006) identified a heterozygous 178G-C transversion in exon 2 of the KRAS2 gene, predicting a gly60-to-arg (G60R) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CARDIOFACIOCUTANEOUS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NOONAN SYNDROME 3, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, ASP153VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894360,
|
|
|
|
|
|
|
|
ClinVar: RCV000013417, RCV000013418, RCV000157940, RCV000212501, RCV000507330, RCV000523200, RCV000763307, RCV000844634, RCV003450634, RCV004018621
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Cardiofaciocutaneous Syndrome 2</em></strong></p><p>
|
|
In 2 unrelated individuals with cardiofaciocutaneous syndrome (CFC2; 615278), Niihori et al. (2006) identified a heterozygous 458A-T transversion in exon 4b of the KRAS2 gene, predicting an asp153-to-val (D153V) substitution. The D153V mutation was identified in DNA extracted from both blood and buccal cells of 1 of the individuals. This heterozygous mutation and G60R (190070.0009) were not found in 100 control chromosomes and were not found in any parent. The results suggested that these germline mutations occurred de novo. </p><p><strong><em>Noonan Syndrome 3</em></strong></p><p>
|
|
Schubbert et al. (2006) found the D153V mutation in a patient who had been diagnosed with Noonan syndrome-3 (NS3; 609942). The 18-year-old male had hypertrophic cardiomyopathy, dysplastic mitral valve with prolapse, Noonan-like features, short stature, mild pectus carinatum, unilateral cryptorchidism, mild developmental delay, and grand mal seizures. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NOONAN SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, THR58ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894364,
|
|
|
|
|
|
|
|
ClinVar: RCV000013419, RCV000157933, RCV000211785, RCV000704828
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-month-old female with Noonan syndrome-3 (NS3; 609942), Schubbert et al. (2006) identified a heterozygous 173C-T transition in the KRAS2 gene, resulting in a thr58-to-ile (T58I) substitution. The child had a severe clinical phenotype and presented with a myeloproliferative disorder of the juvenile myelomonocytic leukemia (JMML; 607785) type. The mutation was present in the patient's buccal cells but was absent in parental DNA. Clinical features included atrial septal defect, ventricular septal defect, valvular pulmonary stenosis, dysmorphic facial features, short stature, webbed neck, severe developmental delay, macrocephaly, and sagittal suture synostosis. </p><p>Kratz et al. (2009) identified a de novo heterozygous T58I mutation in a patient with Noonan syndrome who also had craniosynostosis, suggesting a genotype/phenotype correlation. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 NOONAN SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, VAL14ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894365,
|
|
|
|
|
|
gnomAD: rs104894365,
|
|
|
|
|
|
ClinVar: RCV000013420, RCV000119792, RCV000157945, RCV000212499, RCV000521254, RCV000844637, RCV001266727, RCV001813184
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 unrelated patients with Noonan syndrome-3 (NS3; 609942), Schubbert et al. (2006) identified a heterozygous 40G-A transition in the KRAS2 gene, resulting in a val14-to-ile (V14I) substitution. Each individual showed a mild clinical phenotype, and none had a history of myeloproliferative disorder or cancer. The patients were from a group of Noonan syndrome patients studied who did not have mutation in the PTPN11 gene (176876) </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 CARDIOFACIOCUTANEOUS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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KRAS, PRO34ARG
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<br />
|
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|
SNP: rs104894366,
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|
|
ClinVar: RCV000043674, RCV000207495, RCV000211723, RCV000850569, RCV001851825
|
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|
|
</span>
|
|
</div>
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|
<div>
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<span class="mim-text-font">
|
|
<p>In a 13-year-old female with the diagnosis of cardiofaciocutaneous syndrome (CFC2; 615278), Schubbert et al. (2006) found a heterozygous pro34-to-arg (P34R) mutation in the KRAS2 gene. The patient had pulmonic stenosis, left ventricular hypertrophy, Noonan-like facial features, short stature, short neck, broad thorax, lymphedema, chylothorax, left ptosis, severe developmental delay, and agenesis of the corpus callosum. </p>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>.0014 NOONAN SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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KRAS, VAL152GLY
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<br />
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SNP: rs104894367,
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ClinVar: RCV000013422
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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 1-year-old girl with the diagnosis of Noonan syndrome-3 (NS3; 609942), Carta et al. (2006) identified a 455T-G transversion in the KRAS2 gene, resulting in a val152-to-gly (V152G) substitution. The patient had macrocephaly with high and broad forehead, curly and sparse hair, hypertelorism, strabismus, epicanthic folds, downslanting palpebral fissures, hypoplastic nasal bridge with bulbous tip of the nose, high palate and macroglossia, low-set and posteriorly rotated ears, short neck with redundant skin, wide-set nipples, and umbilical hernia. She had been born at 32 weeks' gestation by cesarean section after a pregnancy complicated by a cystic hygroma detected at 12 weeks and polyhydramnios at 30 weeks. At birth she showed edema of the lower limbs. The phenotype showed features overlapping Costello syndrome (218040) (polyhydramnios, neonatal macrosomia, and macrocephaly, loose skin, and severe failure to thrive) and, to a lesser extent, CFC syndrome (615278) (macrocephaly and sparse hair). </p>
|
|
</span>
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|
</div>
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<div>
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<br />
|
|
</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 NOONAN SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
KRAS, ASP153VAL
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<br />
|
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ClinVar: RCV000013417, RCV000013418, RCV000157940, RCV000212501, RCV000507330, RCV000523200, RCV000763307, RCV000844634, RCV003450634, RCV004018621
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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 14-year-old girl with Noonan syndrome-3 (NS3; 609942) and some features of CFC syndrome (615278), Carta et al. (2006) identified a 458A-T transversion in the KRAS2 gene, resulting in an asp153-to-val (D153V) substitution. The girl had short stature and growth retardation and delayed bone age, cardiac defects (moderate ventricular hypertrophy, mild pulmonic stenosis, and atrial septal defect), dysmorphic features (hypertelorism, downslanting palpebral fissures, strabismus, low-set and thick ears, relative macrocephaly with high forehead, and a depressed nasal bridge), short and mildly webbed neck, wide-set nipples, and developmental delay. There was hyperpigmentation of the skin and a large cafe-au-lait spot on the face. Gestation was complicated by polyhydramnios. </p>
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|
</span>
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|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 PILOCYTIC ASTROCYTOMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, GLY13ARG
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|
<br />
|
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|
|
SNP: rs121913535,
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|
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|
|
|
gnomAD: rs121913535,
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|
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|
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ClinVar: RCV000013424, RCV000038267, RCV001357137
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 21 sporadic pilocytic astrocytoma (PA) (see 137800) samples, Sharma et al. (2005) identified a G-to-C transversion in the KRAS2 gene, resulting in a gly13-to-arg (G13R) substitution. The tumor arose in the cortex of an 11-year-old boy; the mutation was not identified in the germline of the patient. Immunohistochemical studies showed increased phospho-AKT (see 164730) activity compared to controls in all 21 PA samples, indicating increased activation of the Ras pathway. No mutations in the KRAS gene were observed in the other tumors, and none of the 21 tumors showed mutations in the HRAS (190020) or NRAS (164790) genes. Of note, the G13R substitution occurs in the same codon as another KRAS mutation (G13D; 190070.0003) identified in a breast carcinoma cell line. </p>
|
|
</span>
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</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 CARDIOFACIOCUTANEOUS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, LYS5ASN
|
|
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|
|
<br />
|
|
|
|
SNP: rs104894361,
|
|
|
|
|
|
gnomAD: rs104894361,
|
|
|
|
|
|
ClinVar: RCV000013425, RCV000153427, RCV000520745, RCV000623267
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7.5-month-old male infant with a clinical diagnosis of Costello syndrome (218040), Zenker et al. (2007) identified a heterozygous 15A-T transversion in exon 1 of the KRAS2 gene, resulting in a lys5-to-asn (K5N) substitution. The patient had hypertelorism, downslanting palpebral fissures, coarse facies, pectus carinatum, sparse hair, redundant skin, and moderate mental retardation. Zenker et al. (2007) noted that the patient may later develop features of cardiofaciocutaneous syndrome (CFC2; 615278), which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders. </p><p>Kerr et al. (2008) commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (190020). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 CARDIOFACIOCUTANEOUS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, PHE156LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894362,
|
|
|
|
|
|
|
|
ClinVar: RCV000013426, RCV000157942, RCV001205658, RCV004549359
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male infant with a clinical diagnosis of Costello syndrome (218040) who died suddenly at age 14 months, Zenker et al. (2007) identified a heterozygous 468C-G transversion in the KRAS2 gene, resulting in a phe156-to-leu (F156L) substitution. The patient had coarse facies, cardiac defects, sparse hair, loose and redundant skin, developmental delay, and moderate mental retardation. Zenker et al. (2007) noted that the patient may later develop features of cardiofaciocutaneous syndrome (CFC2; 615278), which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders. </p><p>Kerr et al. (2008) commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (190020). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 NOONAN SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, LYS5GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs193929331,
|
|
|
|
|
|
|
|
ClinVar: RCV000013427, RCV000149836, RCV000364781, RCV000605141, RCV002291547, RCV004549360
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 20-year-old woman with clinical features typical of Costello syndrome (218040) and additional findings seen in Noonan syndrome (NS3; 609942), Bertola et al. (2007) identified a 194A-G transition in exon 2 of the KRAS gene, resulting in a lys5-to-glu (K5E) substitution. The mutation was not found in her unaffected mother or brother or in 100 controls. </p><p>Kerr et al. (2008) commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (190020). </p><p>Bertola et al. (2012) reported a patient with a germline K5E mutation and dysmorphic features who developed multiple diffuse schwannomas. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 NOONAN SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, GLY60SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894359,
|
|
|
|
|
|
|
|
ClinVar: RCV000013428, RCV000157934, RCV000689097, RCV002470709
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Noonan syndrome-3 (NS3; 609942) and craniosynostosis, Kratz et al. (2009) identified a de novo heterozygous 178G-A transition in the KRAS gene, resulting in a gly60-to-ser (G60S) substitution. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure. </p><p>A mutation in this same codon (G60R; 190070.0009) has been found in a patient with cardiofaciocutaneous syndrome (CFC2; 615278).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 CARDIOFACIOCUTANEOUS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, TYR71HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907205,
|
|
|
|
|
|
|
|
ClinVar: RCV000024617
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son with variable features of cardiofaciocutaneous syndrome (CFC2; 615278), Stark et al. (2012) identified a heterozygous 211T-C transition in exon 3 of the KRAS gene, resulting in a tyr71-to-his (Y71H) substitution in a highly conserved residue close to a region that is important for effector and regulator binding. The mutation was not found in 500 control individuals and was shown by in vitro studies to increase effector affinity. The son had delayed psychomotor development and a distinctive appearance, including curly hair, absent eyebrows, and broad forehead. Echocardiogram was normal at age 3 years. His mother had a similar physical appearance and also had high-arched palate, myopia, and mitral valve prolapse. She had attended a school for children with special needs. Both patients showed signs of a peripheral sensorimotor axonal neuropathy, more severe in the mother, who developed Charcot arthropathy of the feet. PMP22 (601097) testing in the mother was negative, but an additional cause of the neuropathy could not be excluded. The authors stated that this was the first documented vertically transmitted KRAS mutation. </p><p>Y71 is located at the end of the switch II region of KRAS. Using in vitro assays and transfected COS-7 cells, Cirstea et al. (2013) found that the Y71H mutation increased the binding affinity of KRAS for its major effector, RAF1 kinase (164760), leading to increased activation of MEK1 (176872)/MEK2 (601263) and ERK1 (601795)/ERK2 (176948), irrespective of stimulation. The mutation did not alter the rate of nucleotide dissociation by KRAS. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 CARDIOFACIOCUTANEOUS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, LYS147GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907206,
|
|
|
|
|
|
|
|
ClinVar: RCV000024618, RCV000520244
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with variable features of cardiofaciocutaneous syndrome (CFC2; 615278), Stark et al. (2012) identified a de novo heterozygous 439A-G transition in exon 4 of the KRAS gene, resulting in a lys147-to-glu (K147E) substitution in a highly conserved residue close to known mutations. Lys147 is part of a motif involved in the binding network for guanine nucleotides, which determine the activation state of RAS proteins. In vitro studies demonstrated that the K147E mutant protein predominates in the active GTP-bound form, probably due to facilitated uncatalyzed GDP/GTP exchange. The patient was 1 of a female dizygotic twin pair; the other twin was unaffected. The patient had a high birth weight, macrocephaly, and abnormal craniofacial features, including proptosis, hypertelorism, downslanting palpebral fissures, low-set ears, and short neck, suggestive of Noonan syndrome. Reexamination at age 3.5 years showed coarser facial features more consistent with CFC. She also had hypertrophy of the interventricular myocardial septum, myocardial hypertrophy, and pulmonic stenosis. She had mildly delayed development. </p><p>K147 is a conserved amino acid within a motif required for guanine base binding by KRAS. K147 is also ubiquitinated, leading to increased KRAS activation by GEF proteins. Using in vitro assays and transfected COS-7 cells, Cirstea et al. (2013) found that the K147E mutation significantly increased nucleotide dissociation in KRAS, generating a self-activating protein that acted independently of upstream signaling. However, overactivity of K147E mutant KRAS was subject to normal downregulation by RasGAP (see 139150) and had 2-fold lower affinity for RAF1 kinase (164760). </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, GLY13CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913535,
|
|
|
|
|
|
gnomAD: rs121913535,
|
|
|
|
|
|
ClinVar: RCV000038268, RCV000144972, RCV000681039, RCV003335071
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous c.37G-T transversion in the KRAS gene, resulting in a gly13-to-cys (G13C) substitution. Cells transfected with the mutations showed an increase in active RAS compared to controls, consistent with a gain of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 OCULOECTODERMAL SYNDROME, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KRAS, LEU19PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913538,
|
|
|
|
|
|
gnomAD: rs121913538,
|
|
|
|
|
|
ClinVar: RCV000201922, RCV001839449, RCV003654222
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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<p>In a 25-year-old man with oculoectodermal syndrome (OES; 600268), who was one of the original boys (patient 2) with OES described by Toriello et al. (1993), Peacock et al. (2015) identified heterozygosity for a somatic c.57G-C transversion (c.57G-C, NM_033360.3) in the KRAS gene, resulting in a leu19-to-phe (L19F) substitution (allelic frequency, 16.9%). The mutation was also found in samples from the patient's skin, bone marrow from proximal femur, and peripheral blood (allelic frequencies, 4.7-10.3%). </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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<h4>
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<span class="mim-font">
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<strong>.0025 ARTERIOVENOUS MALFORMATION OF THE BRAIN, 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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KRAS, GLY12ASP
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<br />
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ClinVar: RCV000013411, RCV000022799, RCV000029214, RCV000029215, RCV000144969, RCV000144970, RCV000150896, RCV000150897, RCV000272938, RCV000433573, RCV000548006, RCV000585796, RCV000662266, RCV000856666, RCV001799604, RCV001839445, RCV002508117, RCV003327361, RCV004018620, RCV004554600, RCV004668724, RCV005007840
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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>Using exome DNA sequencing and droplet digital PCR analysis, Nikolaev et al. (2018) identified a gly12-to-asp (G12D, c.35G-A) mutation in a total of 32 of 72 arteriovenous malformations of the brain (BAVM; 108010), and in none of 21 paired blood samples. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12V variant (190070.0026) were present in 2.4 to 4.0% of the sequence reads per sample. The G12D mutation drove MAPK-ERK activity in endothelial cells. </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 ARTERIOVENOUS MALFORMATION OF THE BRAIN, 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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KRAS, GLY12VAL
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<br />
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ClinVar: RCV000013413, RCV000029216, RCV000150895, RCV000154262, RCV000157944, RCV000585801, RCV002291496, RCV003322589, RCV003455987, RCV003539760, RCV004668725
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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>Using exome DNA sequencing and droplet digital PCR analysis, Nikolaev et al. (2018) identified a gly12-to-val (G12D, c.35G-T) mutation in a total of 13 of 72 arteriovenous malformations of the brain (BAVM; 108010), and in none of 21 paired blood samples. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12D variant (190070.0025) were present in 2.4 to 4.0% of the sequence reads per sample. The G12V mutation drove MAPK-ERK activity in endothelial cells. </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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<h4>
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<span class="mim-font">
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<strong>.0027 OCULOECTODERMAL SYNDROME, 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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KRAS, ALA146THR
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<br />
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SNP: rs121913527,
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ClinVar: RCV000178223, RCV000791298, RCV001839448, RCV001852208, RCV002227934, RCV004554743
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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 lesional tissues from a 6-year-old boy with oculoectodermal syndrome (OES; 600268), originally reported by Aslan et al. (2014), Boppudi et al. (2016) identified somatic mosaicism for a c.436G-A transition (c.436G-A, ENST00000311936) in the KRAS gene, resulting in an ala146-to-thr (A146T) substitution. The mutant allele frequency ranged from 11% to 38% in lesional tissue samples, and was not found in leukocyte DNA. </p><p>In a 4-year-old Mexican girl with OES (patient 1), Chacon-Camacho et al. (2019) identified somatic mosaicism for the A146T mutation in the KRAS gene. The mutant allele frequency was 28% in lesional tissue, and the variant was not detected in DNA isolated from blood leukocytes or buccal cells. </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>.0028 OCULOECTODERMAL SYNDROME, 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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KRAS, ALA146VAL
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<br />
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SNP: rs1057519725,
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ClinVar: RCV000791299, RCV001839452, RCV002524688, RCV003332167, RCV003488585, RCV004760489
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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 children with oculoectodermal syndrome (OES; 600268), Boppudi et al. (2016) identified somatic mosaicism for a c.437C-T transition (c.437C-T, ENST00000311936) in the KRAS gene, resulting in an ala146-to-val (A146V) substitution. The mutant allele frequency ranged from less than 10% to 40% in lesional tissue samples, and was not found in leukocyte DNA. </p><p>In a 12-year-old Mexican boy with OES (patient 2), Chacon-Camacho et al. (2019) identified somatic mosaicism for the A146V mutation in the KRAS gene. The mutant allele frequency was 26% to 27% in lesional tissues, and the variant was not detected in DNA isolated from blood leukocytes or buccal cells. </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>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Capon et al. (1983); Der and Cooper (1983); Sakaguchi et al. (1984);
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Shimizu et al. (1983)
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</span>
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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>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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<strong>Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung.</strong>
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Cancer 92: 1525-1530, 2001.
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<strong>Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.</strong>
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Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y.
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<strong>Germline mutations in HRAS proto-oncogene cause Costello syndrome.</strong>
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Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., Lanman, B. A., Werner, J., and 22 others.
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<strong>The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.</strong>
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Capon, D. J., Seeburg, P. H., McGrath, J. P., Hayflick, J. S., Edman, U., Levinson, A. D., Goeddel, D. V.
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<strong>Activation of Ki-ras2 gene in human colon and lung carcinomas by two different point mutations.</strong>
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Nature 304: 507-513, 1983.
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Sonja A. Rasmussen - updated : 07/25/2022<br>Bao Lige - updated : 03/09/2022<br>Ada Hamosh - updated : 05/13/2020<br>Ada Hamosh - updated : 12/10/2019<br>Ada Hamosh - updated : 09/12/2019<br>Marla J. F. O'Neill - updated : 08/01/2019<br>Ada Hamosh - updated : 03/06/2018<br>Ada Hamosh - updated : 09/30/2016<br>Ada Hamosh - updated : 02/17/2016<br>Nara Sobreira - updated : 11/11/2015<br>Cassandra L. Kniffin - updated : 11/12/2014<br>Patricia A. Hartz - updated : 5/23/2014<br>Ada Hamosh - updated : 12/6/2013<br>Ada Hamosh - updated : 7/9/2013<br>Ada Hamosh - updated : 7/8/2013<br>Cassandra L. Kniffin - updated : 1/30/2013<br>Cassandra L. Kniffin - updated : 7/25/2012<br>Ada Hamosh - updated : 7/17/2012<br>Cassandra L. Kniffin - updated : 6/28/2012<br>Marla J. F. O'Neill - updated : 11/29/2011<br>Cassandra L. Kniffin - updated : 2/21/2011<br>Ada Hamosh - updated : 2/3/2011<br>Ada Hamosh - updated : 8/17/2010<br>Ada Hamosh - updated : 3/9/2010<br>Ada Hamosh - updated : 12/29/2009<br>Cassandra L. Kniffin - updated : 10/27/2009<br>Ada Hamosh - updated : 10/13/2009<br>Marla J. F. O'Neill - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 3/3/2009<br>Ada Hamosh - updated : 1/20/2009<br>Ada Hamosh - updated : 7/29/2008<br>Cassandra L. Kniffin - updated : 3/17/2008<br>Ada Hamosh - updated : 11/12/2007<br>George E. Tiller - updated : 4/5/2007<br>Cassandra L. Kniffin - reorganized : 3/8/2007<br>Cassandra L. Kniffin - updated : 3/2/2007<br>Cassandra L. Kniffin - updated : 2/15/2007<br>Ada Hamosh - updated : 2/8/2007<br>Ada Hamosh - updated : 11/28/2006<br>Victor A. McKusick - updated : 6/13/2006<br>Patricia A. Hartz - updated : 4/10/2006<br>Patricia A. Hartz - updated : 3/28/2006<br>Victor A. McKusick - updated : 2/24/2006<br>Ada Hamosh - updated : 9/7/2005<br>Stylianos E. Antonarakis - updated : 3/28/2005<br>Marla J. F. O'Neill - updated : 3/22/2005<br>Victor A. McKusick - updated : 12/16/2003<br>John A. Phillips, III - updated : 9/2/2003<br>John A. Phillips, III - updated : 9/2/2003<br>Ada Hamosh - updated : 9/17/2002<br>Victor A. McKusick - updated : 8/15/2002<br>Victor A. McKusick - updated : 12/13/2001<br>Victor A. McKusick - updated : 9/26/2001<br>Victor A. McKusick - updated : 9/4/2001<br>Victor A. McKusick - updated : 8/24/2001<br>Ada Hamosh - updated : 4/23/2001<br>Ada Hamosh - updated : 4/28/2000<br>Ada Hamosh - updated : 2/11/2000<br>Paul Brennan - updated : 7/31/1998<br>Victor A. McKusick - updated : 3/27/1998<br>Paul Brennan - updated : 11/14/1997<br>Victor A. McKusick - edited : 3/3/1997<br>Mark H. Paalman - edited : 1/10/1997
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Creation Date:
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Victor A. McKusick : 6/2/1986
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Edit History:
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carol : 07/26/2022<br>carol : 07/25/2022<br>carol : 05/04/2022<br>carol : 04/19/2022<br>mgross : 03/09/2022<br>carol : 11/04/2021<br>carol : 01/14/2021<br>alopez : 06/22/2020<br>alopez : 05/13/2020<br>alopez : 12/10/2019<br>carol : 10/02/2019<br>alopez : 09/12/2019<br>alopez : 08/01/2019<br>alopez : 08/01/2019<br>carol : 07/24/2019<br>carol : 07/23/2019<br>carol : 03/07/2018<br>alopez : 03/06/2018<br>carol : 08/24/2017<br>alopez : 09/30/2016<br>carol : 09/02/2016<br>alopez : 02/17/2016<br>carol : 11/11/2015<br>alopez : 8/31/2015<br>carol : 11/18/2014<br>mcolton : 11/13/2014<br>ckniffin : 11/12/2014<br>mgross : 5/23/2014<br>mgross : 5/23/2014<br>mcolton : 5/22/2014<br>mcolton : 5/22/2014<br>alopez : 12/6/2013<br>alopez : 7/9/2013<br>alopez : 7/9/2013<br>alopez : 7/8/2013<br>alopez : 6/20/2013<br>alopez : 2/6/2013<br>ckniffin : 1/30/2013<br>carol : 7/26/2012<br>carol : 7/26/2012<br>carol : 7/25/2012<br>ckniffin : 7/25/2012<br>alopez : 7/19/2012<br>terry : 7/17/2012<br>terry : 7/3/2012<br>carol : 7/2/2012<br>ckniffin : 6/28/2012<br>terry : 4/9/2012<br>alopez : 3/7/2012<br>carol : 12/8/2011<br>carol : 11/29/2011<br>terry : 3/10/2011<br>wwang : 3/1/2011<br>ckniffin : 2/21/2011<br>alopez : 2/7/2011<br>alopez : 2/7/2011<br>alopez : 2/7/2011<br>alopez : 2/7/2011<br>terry : 2/3/2011<br>terry : 11/3/2010<br>alopez : 8/20/2010<br>terry : 8/17/2010<br>alopez : 3/9/2010<br>terry : 3/9/2010<br>alopez : 1/6/2010<br>terry : 12/29/2009<br>carol : 11/23/2009<br>carol : 11/23/2009<br>wwang : 11/6/2009<br>ckniffin : 10/27/2009<br>alopez : 10/23/2009<br>terry : 10/13/2009<br>joanna : 9/14/2009<br>wwang : 6/3/2009<br>terry : 6/1/2009<br>wwang : 3/5/2009<br>ckniffin : 3/3/2009<br>alopez : 2/6/2009<br>carol : 2/6/2009<br>terry : 1/20/2009<br>alopez : 7/31/2008<br>terry : 7/29/2008<br>wwang : 3/19/2008<br>ckniffin : 3/17/2008<br>alopez : 11/14/2007<br>alopez : 11/14/2007<br>terry : 11/12/2007<br>carol : 9/10/2007<br>carol : 9/6/2007<br>alopez : 4/13/2007<br>terry : 4/5/2007<br>carol : 3/8/2007<br>carol : 3/8/2007<br>ckniffin : 3/8/2007<br>ckniffin : 3/2/2007<br>wwang : 2/19/2007<br>ckniffin : 2/15/2007<br>alopez : 2/8/2007<br>alopez : 2/8/2007<br>alopez : 2/8/2007<br>terry : 2/1/2007<br>alopez : 12/7/2006<br>terry : 11/28/2006<br>alopez : 6/16/2006<br>terry : 6/13/2006<br>mgross : 4/14/2006<br>terry : 4/10/2006<br>wwang : 3/30/2006<br>terry : 3/28/2006<br>alopez : 3/3/2006<br>terry : 2/24/2006<br>alopez : 9/14/2005<br>terry : 9/7/2005<br>alopez : 7/14/2005<br>carol : 5/27/2005<br>mgross : 3/28/2005<br>tkritzer : 3/22/2005<br>tkritzer : 12/16/2003<br>cwells : 11/6/2003<br>alopez : 9/2/2003<br>alopez : 9/2/2003<br>terry : 1/2/2003<br>terry : 11/22/2002<br>alopez : 9/17/2002<br>tkritzer : 8/21/2002<br>tkritzer : 8/19/2002<br>terry : 8/15/2002<br>terry : 3/5/2002<br>alopez : 2/5/2002<br>alopez : 1/22/2002<br>carol : 1/3/2002<br>mcapotos : 12/19/2001<br>terry : 12/13/2001<br>carol : 10/4/2001<br>mcapotos : 10/3/2001<br>terry : 9/26/2001<br>alopez : 9/4/2001<br>alopez : 8/27/2001<br>terry : 8/24/2001<br>alopez : 4/25/2001<br>terry : 4/23/2001<br>alopez : 5/1/2000<br>terry : 4/28/2000<br>alopez : 2/15/2000<br>terry : 2/11/2000<br>mgross : 6/22/1999<br>alopez : 9/22/1998<br>alopez : 9/22/1998<br>terry : 7/24/1998<br>dkim : 7/23/1998<br>psherman : 3/27/1998<br>dholmes : 3/6/1998<br>alopez : 11/26/1997<br>alopez : 11/26/1997<br>alopez : 11/17/1997<br>alopez : 11/17/1997<br>alopez : 11/17/1997<br>alopez : 11/14/1997<br>mark : 3/3/1997<br>mark : 1/10/1997<br>mark : 1/10/1997<br>terry : 11/6/1996<br>terry : 10/31/1996<br>mark : 8/10/1995<br>mimadm : 6/7/1995<br>carol : 11/1/1993<br>carol : 6/30/1993<br>carol : 6/22/1993<br>carol : 6/7/1993
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