3717 lines
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Entry
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- *105590 - ALK RECEPTOR TYROSINE KINASE; ALK
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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">*105590</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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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</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="#geneFunction">Gene Function</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="#cytogenetics">Cytogenetics</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="#animalModel">Animal Model</a>
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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/105590">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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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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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000171094;t=ENST00000389048" 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=238" 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=105590" 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=ENSG00000171094;t=ENST00000389048" 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_001353765,NM_004304,XR_001738688" 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_004304" 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=105590" 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=00104&isoform_id=00104_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/ALK" 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/1848244,2454168,29029632,62088534,62198450,62630147,62702200,62822479,119620911,119620912,119620913,187384818,187384822,187384824,187384826,187384828,187384830,187384832,187384836,187384838,187938336,187938338,194382374,209484229,209484233,209484235,209484239,209484241,209484243,209554648,209554650,218055951,267822896,267822898,267822900,267822902,267822904,267822906,269999940,269999942,296439447,475869912,924442208,1219456112,2462571573,2797140466" 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/Q9UM73" 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=238" 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=ENSG00000171094;t=ENST00000389048" 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=ALK" 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=ALK" 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+238" 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/ALK" 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:238" 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/238" 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=chr2&hgg_gene=ENST00000389048.8&hgg_start=29192774&hgg_end=29921586&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:427" 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:427" 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=105590[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=105590[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://gnomad.broadinstitute.org/gene/ENSG00000171094" 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=ALK" 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=ALK" 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=ALK" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ALK&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/PA24719" 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:427" 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/FBgn0040505.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:103305" 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/ALK#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:103305" 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/238/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://www.orthodb.org/?ncbi=238" 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=WBGene00004740;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-030616-115" 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">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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|
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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:238" 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=ALK&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">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
105590
|
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</span>
|
|
</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>
|
|
<span class="mim-font">
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|
ALK RECEPTOR TYROSINE KINASE; ALK
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|
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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 />
|
|
</div>
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<div>
|
|
<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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
ANAPLASTIC LYMPHOMA KINASE
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
|
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
ALK/EML4 FUSION GENE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
ALK/NPM1 FUSION GENE, INCLUDED<br />
|
|
ALK/RNF213 FUSION GENE, INCLUDED<br />
|
|
ALK/CARS FUSION GENE, INCLUDED<br />
|
|
ALK/CLTC FUSION GENE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ALK" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ALK</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
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|
|
|
|
|
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|
|
<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/2/157?start=-3&limit=10&highlight=157">2p23.2-p23.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:29192774-29921586&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'})">2:29,192,774-29,921,586</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<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">
|
|
<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="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/157?start=-3&limit=10&highlight=157">
|
|
2p23.2-p23.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Neuroblastoma, susceptibility to, 3}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613014"> 613014 </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>
|
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|
</tr>
|
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<p>The ALK gene encodes a receptor tyrosine kinase that plays a role in regulation of Wnt/beta-catenin (see <a href="/entry/116806">116806</a>) signaling and is involved in the development of many cancer types, especially non-small-cell lung cancer (NSCLC) (summary by <a href="#13" class="mim-tip-reference" title="Majumder, P., Chanda, K., Das, D., Singh, B. K., Chakrabarti, P., Jana, N. R., Mukhopadhyay, D. <strong>A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer's disease and type 2 diabetes.</strong> Biochem. J. 478: 3297-3317, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34409981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34409981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34409981[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/10.1042/BCJ20210175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34409981">Majumder et al., 2021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34409981" 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>Large-cell lymphomas comprise approximately 25% of all non-Hodgkin lymphomas in children and young adults, and approximately one-third of these tumors have a t(2;5)(p23;q35) translocation. By a positional cloning strategy, <a href="#15" class="mim-tip-reference" title="Morris, S. W., Kirstein, M. N., Valentine, M. B., Dittmer, K. G., Shapiro, D. N., Saltman, D. L., Look, A. T. <strong>Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.</strong> Science 263: 1281-1284, 1994. Note: Erratum: Science 267: 316-317, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8122112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8122112</a>] [<a href="https://doi.org/10.1126/science.8122112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8122112">Morris et al. (1994)</a> demonstrated that the rearrangement fused the nucleophosmin gene (NPM1; <a href="/entry/164040">164040</a>), located on 5q35, to a previously unidentified protein tyrosine kinase gene, which they called anaplastic lymphoma kinase (ALK), located on 2p23. In the predicted hybrid protein, the amino terminus of nucleophosmin is linked to the catalytic domain of ALK. Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases (see INSR; <a href="/entry/147670">147670</a>). Unscheduled expression of the truncated ALK was thought to contribute to malignant transformation in these lymphomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8122112" 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="#1" class="mim-tip-reference" title="Benharroch, D., Meguerian-Bedoyan, Z., Lamant, L., Amin, C., Brugieres, L., Terrier-Lacombe, M.-J., Haralambieva, E., Pulford, K., Pileri, S., Morris, S. W., Mason, D. Y., Delsol, G. <strong>ALK-positive lymphoma: a single disease with a broad spectrum of morphology.</strong> Blood 91: 2076-2084, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490693</a>]" pmid="9490693">Benharroch et al. (1998)</a> studied the morphologic and phenotypic spectrum of 123 cases of lymphoma, all of which expressed ALK protein. They provided strong evidence that the morphologic patterns of anaplastic large-cell lymphoma (ALCL), described in previous reports as representing possible subtypes of ALCL, are in fact morphologic variants of the same disease entity. They concluded that ALK-positive neoplasms represent a distinct entity. Because the morphology of the tumors is often neither anaplastic nor large cell, the authors suggested that the tumors should be referred to as ALK lymphomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9490693" 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 secreted protein 'Jelly belly' (Jeb) is required for an essential signaling event in Drosophila muscle development. In the absence of functional Jeb, visceral muscle precursors are normally specified but fail to migrate and differentiate. <a href="#10" class="mim-tip-reference" title="Lee, H.-H., Norris, A., Weiss, J. B., Frasch, M. <strong>Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers.</strong> Nature 425: 507-512, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14523446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14523446</a>] [<a href="https://doi.org/10.1038/nature01916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14523446">Lee et al. (2003)</a> demonstrated that the Jeb receptor is the Drosophila homolog of ALK. In Drosophila, localized Jeb activates Alk and the downstream Ras/mitogen-activated protein kinase cascade to specify a select group of visceral muscle precursors as muscle-patterning pioneers. Jeb/Alk signaling induces the myoblast fusion gene 'dumbfounded' (duf; also known as kirre; see <a href="/entry/607761">607761</a>) as well as org1, a Drosophila homolog of mammalian TBX1 (<a href="/entry/602054">602054</a>), in these cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14523446" 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="Englund, C., Loren, C. E., Grabbe, C., Varshney, G. K., Deleuil, F., Hallberg, B., Palmer, R. H. <strong>Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion.</strong> Nature 425: 512-516, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14523447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14523447</a>] [<a href="https://doi.org/10.1038/nature01950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14523447">Englund et al. (2003)</a> also showed that Drosophila Alk is the receptor for Jeb in the developing visceral mesoderm and that Jeb binding stimulates an Alk-driven extracellular signal-regulated kinase-mediated signaling pathway, which results in the expression of the downstream gene duf, which is needed for muscle fusion. This new signal transduction pathway drives specification of the muscle founder cells, and the regulation of duf expression by Drosophila Alk/RTK explains the visceral-mesoderm-specific muscle fusion defects observed in both Alk and Jeb mutant animals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14523447" 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 expression profiling of ALK-positive ALCLs, <a href="#18" class="mim-tip-reference" title="Piva, R., Pellegrino, E., Mattioli, M., Agnelli, L., Lombardi, L., Boccalatte, F., Costa, G., Ruggeri, B. A., Cheng, M., Chiarle, R., Palestro, G., Neri, A., Inghirami, G. <strong>Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCL2A1 as critical target genes.</strong> J. Clin. Invest. 116: 3171-3182, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17111047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17111047</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17111047[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI29401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17111047">Piva et al. (2006)</a> identified a large group of ALK-regulated genes. Functional RNA interference screening on a set of these transcriptional targets revealed that CEBPB (<a href="/entry/189965">189965</a>) and BCL2A1 (<a href="/entry/601056">601056</a>) were absolutely necessary to induce cell transformation and/or to sustain growth and survival of ALK-positive ALCL cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17111047" 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>IL22R1 (<a href="/entry/605457">605457</a>) is not expressed on normal leukocytes, but it is expressed on T-cells from ALK-positive ALCL patients. <a href="#19" class="mim-tip-reference" title="Savan, R., McFarland, A. P., Reynolds, D. A., Feigenbaum, L., Ramakrishnan, K., Karwan, M., Shirota, H., Klinman, D. M., Dunleavy, K., Pittaluga, S., Anderson, S. K., Donnelly, R. P., Wilson, W. H., Young, H. A. <strong>A novel role for IL-22R1 as a driver of inflammation.</strong> Blood 117: 575-584, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20971950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20971950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20971950[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-2010-05-285908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20971950">Savan et al. (2011)</a> found that mice expressing a human IL22R1 transgene on lymphocytes exhibited deterioration of health at 8 to 12 weeks of age and death due to multiorgan inflammation. Transgenic mice developed neutrophilia that correlated with increased circulating Il17 (IL17A; <a href="/entry/603149">603149</a>) and Gcsf (CSF3; <a href="/entry/138970">138970</a>), as well as increased serum Il22 (<a href="/entry/605330">605330</a>). ALK-positive ALCL patients had elevated IL22, IL17, and IL8 (<a href="/entry/146930">146930</a>) before treatment, but those in complete remission after chemotherapy did not have detectable IL22 and IL17. <a href="#19" class="mim-tip-reference" title="Savan, R., McFarland, A. P., Reynolds, D. A., Feigenbaum, L., Ramakrishnan, K., Karwan, M., Shirota, H., Klinman, D. M., Dunleavy, K., Pittaluga, S., Anderson, S. K., Donnelly, R. P., Wilson, W. H., Young, H. A. <strong>A novel role for IL-22R1 as a driver of inflammation.</strong> Blood 117: 575-584, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20971950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20971950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20971950[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-2010-05-285908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20971950">Savan et al. (2011)</a> concluded that IL22R1 and IL22 are involved in inflammation and ALK-positive ALCL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20971950" 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 reciprocal immunoprecipitation of transfected 293T cells, <a href="#21" class="mim-tip-reference" title="Takagi, D., Tatsumi, Y., Yokochi, T., Takatori, A., Ohira, M., Kamijo, T., Kondo, S., Fujii, Y., Nakagawara, A. <strong>Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma.</strong> Cancer Sci. 104: 563-572, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23360421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23360421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23360421[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/10.1111/cas.12115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23360421">Takagi et al. (2013)</a> found that the adaptor protein SHF (<a href="/entry/617313">617313</a>) interacted with ALK. In neuroblastoma cells and patient tissue, ALK and SHF showed an inverse relationship, with high ALK and low SHF mRNA associated with poor prognosis. Overexpression of ALK and knockdown of SHF via short interfering RNA yielded similar and additive results, including increased growth, ALK phosphorylation, and activation of ERK1 (MAPK3; <a href="/entry/601795">601795</a>)/ERK2 (MAPK1; <a href="/entry/176948">176948</a>) and STAT3 (<a href="/entry/102582">102582</a>). Knockdown of SHF also increased mobility and invasiveness of neuroblastoma cells. <a href="#21" class="mim-tip-reference" title="Takagi, D., Tatsumi, Y., Yokochi, T., Takatori, A., Ohira, M., Kamijo, T., Kondo, S., Fujii, Y., Nakagawara, A. <strong>Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma.</strong> Cancer Sci. 104: 563-572, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23360421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23360421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23360421[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/10.1111/cas.12115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23360421">Takagi et al. (2013)</a> concluded that SHF negatively regulates ALK signal transduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23360421" 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="Wiesner, T., Lee, W., Obenauf, A. C., Ran, L., Murali, R., Zhang, Q. F., Wong, E. W. P., Hu, W., Scott, S. N., Shah, R. H., Landa, I., Button, J., and 20 others. <strong>Alternative transcription initiation leads to expression of a novel ALK isoform in cancer.</strong> Nature 526: 453-457, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26444240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26444240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26444240[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/nature15258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26444240">Wiesner et al. (2015)</a> reported a novel isoform of ALK that is expressed in approximately 11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19 and is termed ALK(ATI). In ALK(ATI)-expressing tumors, the ATI site is enriched for H3K4 trimethylation and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes 3 proteins with molecular masses of 61.1, 60.8, and 58.7 kD, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signaling pathways, drives growth factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumors may benefit from ALK inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26444240" 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 Western blot analysis, <a href="#13" class="mim-tip-reference" title="Majumder, P., Chanda, K., Das, D., Singh, B. K., Chakrabarti, P., Jana, N. R., Mukhopadhyay, D. <strong>A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer's disease and type 2 diabetes.</strong> Biochem. J. 478: 3297-3317, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34409981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34409981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34409981[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/10.1042/BCJ20210175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34409981">Majumder et al. (2021)</a> showed that levels of GRB2 (<a href="/entry/108355">108355</a>) and NOX4 (<a href="/entry/605261">605261</a>) were elevated in tissues from mouse models for Alzheimer disease (AD; see <a href="/entry/104300">104300</a>) and type 2 diabetes (T2D; <a href="/entry/125853">125853</a>), as well as in tissues from AD and T2D patients. Knockdown analysis in SHSY-5Y and HepG2 cells revealed that miRNA1271 targeted and restricted expression of ALK and RYK (<a href="/entry/600524">600524</a>), which elevated expression of GRB2 and NOX4. Moreover, PAX4 (<a href="/entry/167413">167413</a>), a transcription factor for both GRB2 and NOX4, was overexpressed during ALK and RYK knockdown due to reduced expression of the PAX4 suppressor ARX (<a href="/entry/300382">300382</a>) via beta-catenin (see <a href="/entry/116806">116806</a>) signaling. In addition, expression of various cytoskeletal proteins was downregulated in liver tissue of T2D patients and in ALK/RYK knockdown cells, but overexpression of GRB2 reversed the cytoskeletal degradation through interaction with NOX4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34409981" 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>ALK/EML4 Fusion Protein</em></strong></p><p>
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<a href="#20" class="mim-tip-reference" title="Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S., Watanabe, H., Kurashina, K., Hatanaka, H., Bando, M., Ohno, S., Ishikawa, Y., Aburatani, H., Niki, T., Sohara, Y., Sugiyama, Y., Mano, H. <strong>Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.</strong> Nature 448: 561-566, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17625570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17625570</a>] [<a href="https://doi.org/10.1038/nature05945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17625570">Soda et al. (2007)</a> showed that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the EML4 gene (<a href="/entry/607442">607442</a>) and the ALK gene in non-small-cell lung cancer (<a href="/entry/211980">211980</a>) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumors in nude mice. <a href="#20" class="mim-tip-reference" title="Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S., Watanabe, H., Kurashina, K., Hatanaka, H., Bando, M., Ohno, S., Ishikawa, Y., Aburatani, H., Niki, T., Sohara, Y., Sugiyama, Y., Mano, H. <strong>Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.</strong> Nature 448: 561-566, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17625570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17625570</a>] [<a href="https://doi.org/10.1038/nature05945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17625570">Soda et al. (2007)</a> detected the ALK-EML4 fusion transcript in 5 of 75 (6.7%) Japanese patients with non-small-cell lung cancer patients examined; none of these patients had a mutation in the epidermal growth factor receptor gene (EGFR; <a href="/entry/131550">131550</a>). The fusion gene encoded a deduced 1,059-amino acid protein with an N-terminal portion (residues 1-496) identical to that of human EML4 and a C-terminal portion (residues 497-1059) identical to the intracellular domain (residues 1058-1620) of human ALK. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17625570" 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 EML4-ALK fusion type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers. <a href="#5" class="mim-tip-reference" title="Choi, Y. L., Soda, M., Yamashita, Y., Ueno, T., Takashima, J., Nakajima, T., Yatabe, Y., Takeuchi, K., Hamada, T., Haruta, H., Ishikawa, Y., Kimura, H., Mitsudomi, T., Tanio, Y., Mano, H. <strong>EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.</strong> New Eng. J. Med. 363: 1734-1739, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20979473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20979473</a>] [<a href="https://doi.org/10.1056/NEJMoa1007478" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20979473">Choi et al. (2010)</a> reported the discovery of 2 secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to 2 different ALK inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20979473" 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>ALK/NPM1 Fusion Protein</em></strong></p><p>
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<a href="#23" class="mim-tip-reference" title="Zhang, Q., Wang, H. Y., Liu, X., Wasik, M. A. <strong>STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression.</strong> Nature Med. 13: 1341-1348, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17922009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17922009</a>] [<a href="https://doi.org/10.1038/nm1659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17922009">Zhang et al. (2007)</a> stated that ALK tyrosine kinase expression is normally confined to neural cells, but chromosomal translocations involving ALK and various partners, most frequently NPM1, result in ectopic expression of ALK in a subset of T-cell lymphomas (TCLs). The NPM1/ALK fusion protein contains the NPM1 oligomerization motif and the ALK catalytic domain, is constitutively activated through autophosphorylation, and mediates malignant cell transformation in vitro and in vivo by activating downstream effectors, including STAT3 (<a href="/entry/102582">102582</a>). <a href="#23" class="mim-tip-reference" title="Zhang, Q., Wang, H. Y., Liu, X., Wasik, M. A. <strong>STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression.</strong> Nature Med. 13: 1341-1348, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17922009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17922009</a>] [<a href="https://doi.org/10.1038/nm1659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17922009">Zhang et al. (2007)</a> found that TCL cell lines expressing NPM1/ALK expressed STAT5B (<a href="/entry/604260">604260</a>), but not STAT5A (<a href="/entry/601511">601511</a>), protein, whereas normal resting and activated T cells from peripheral blood and ALK-negative TCL cell lines expressed STAT5A protein. Activated NPM1/ALK-positive TCL cell lines also did not express STAT5A mRNA, in spite of having an intact STAT5A gene. Analysis of the CpG island in the STAT5A promoter showed that the region was methylated in NPM1/ALK-positive, but not NPM1/ALK-negative, T cells. Chromatin immunoprecipitation analysis revealed that SP1 (<a href="/entry/189906">189906</a>) bound the STAT5A promoter in normal activated T cells, whereas MECP2 (<a href="/entry/300005">300005</a>) bound the promoter of NPM1/ALK-positive TCL cells. Demethylation of the promoter resulted in STAT5A activation and inhibition of NPM1/ALK expression by binding of STAT5A to the NPM1/ALK fusion gene. Expression of NPM1/ALK in NPM1/ALK-negative TCL cells resulted in silencing of STAT5A in a STAT3-dependent manner, whereas small interfering RNA mediated-depletion of NPM1/ALK resulted in STAT5A expression. <a href="#23" class="mim-tip-reference" title="Zhang, Q., Wang, H. Y., Liu, X., Wasik, M. A. <strong>STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression.</strong> Nature Med. 13: 1341-1348, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17922009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17922009</a>] [<a href="https://doi.org/10.1038/nm1659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17922009">Zhang et al. (2007)</a> concluded that NPM1/ALK induces epigenetic silencing of the STAT5A gene and that the STAT5A protein can act as a tumor suppressor by inhibiting NPM1/ALK expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17922009" 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="#16" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. <strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong> Nature 455: 930-935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[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/nature07261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724359">Mosse et al. (2008)</a> stated that the ALK gene comprises 29 coding exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18724359" 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="#15" class="mim-tip-reference" title="Morris, S. W., Kirstein, M. N., Valentine, M. B., Dittmer, K. G., Shapiro, D. N., Saltman, D. L., Look, A. T. <strong>Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.</strong> Science 263: 1281-1284, 1994. Note: Erratum: Science 267: 316-317, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8122112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8122112</a>] [<a href="https://doi.org/10.1126/science.8122112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8122112">Morris et al. (1994)</a> identified the ALK gene on chromosome 2p23 by positional cloning using a t(2;5)(p23;q35) translocation. <a href="#14" class="mim-tip-reference" title="Mathew, P., Morris, S. W., Kane, J. R., Shurtleff, S. A., Pasquini, M., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. <strong>Localization of the murine homolog of the anaplastic lymphoma kinase (Alk) gene on mouse chromosome 17.</strong> Cytogenet. Cell Genet. 70: 143-144, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7736780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7736780</a>] [<a href="https://doi.org/10.1159/000134080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7736780">Mathew et al. (1995)</a> mapped the mouse homolog to chromosome 17 by interspecific backcross analysis, thus confirming the homology between the portion of distal mouse 17 and the short arm of human chromosome 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8122112+7736780" 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>In 2 patients with ALK-positive anaplastic large-cell lymphoma (ALCL) and a third patient with ALK-negative inflammatory myofibroblastic tumors (IMT), <a href="#6" class="mim-tip-reference" title="Cools, J., Wlodarska, I., Somers, R., Mentens, N., Pedeutour, F., Maes, B., De Wolf-Peeters, C., Pauwels, P., Hagemeijer, A., Marynen, P. <strong>Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor.</strong> Genes Chromosomes Cancer 34: 354-362, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112524</a>] [<a href="https://doi.org/10.1002/gcc.10033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112524">Cools et al. (2002)</a> identified novel rearrangements involving the ALK gene. One ALCL patient had a t(2;17)(p23;q25) that resulted in fusion of exons of the ALO17 gene (RNF213; <a href="/entry/613768">613768</a>) to exons of the ALK gene. The other ALCL patient had an unknown karyotype that led to fusion of exons of the CLTC gene (<a href="/entry/118955">118955</a>) to exons of the ALK gene. The IMT patient had a t(2;11;2)(p23;p15;q31) that resulted in fusion of exons of the CARS gene (<a href="/entry/123859">123859</a>) to exons of the ALK gene. The predicted fusion proteins contain 1,172 N-terminal amino acids of ALO17, 1,634 N-terminal amino acids of CLTC, or 606 N-terminal amino acids of CARS fused in frame to the same 562 amino acids of ALK, including the ALK kinase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112524" 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="#16" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. <strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong> Nature 455: 930-935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[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/nature07261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724359">Mosse et al. (2008)</a> identified 3 separate germline missense mutations in the tyrosine kinase domain of the ALK gene (<a href="#0001">105590.0001</a>-<a href="#0003">105590.0003</a>) that segregated with the disease in 8 separate families with neuroblastoma (NBLST3; <a href="/entry/613014">613014</a>). There was incomplete penetrance. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of the samples. Nine of the 10 mutations mapped to critical regions of the kinase domain and were predicted with high probability to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK mRNA resulted in profound inhibition of growth in all cell lines harboring mutant or amplified ALK, as well as in 2 of 6 wildtype cell lines for ALK. <a href="#16" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. <strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong> Nature 455: 930-935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[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/nature07261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724359">Mosse et al. (2008)</a> concluded that heritable mutations of ALK are the main cause of susceptibility to the development of neuroblastoma within families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18724359" 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="Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O. <strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong> Nature 455: 967-970, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923523</a>] [<a href="https://doi.org/10.1038/nature07398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923523">Janoueix-Lerosey et al. (2008)</a> conducted a genomewide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the ALK tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumor DNAs, they identified somatic mutations of the ALK kinase domain that mainly clustered in 2 hotspots. Germline mutations were observed in 2 neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated, and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wildtype ALK, led to a marked decrease of cell proliferation. Altogether, <a href="#9" class="mim-tip-reference" title="Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O. <strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong> Nature 455: 967-970, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923523</a>] [<a href="https://doi.org/10.1038/nature07398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923523">Janoueix-Lerosey et al. (2008)</a> concluded that their data identified ALK as critical player in neuroblastoma development that may represent a therapeutic target. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923523" 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 genomewide scan of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, <a href="#3" class="mim-tip-reference" title="Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S. <strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong> Nature 455: 971-974, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923524</a>] [<a href="https://doi.org/10.1038/nature07399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923524">Chen et al. (2008)</a> identified the ALK locus as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed 8 novel missense mutations in 13 of 215 (6.1%) fresh tumors and 8 of 24 (33%) neuroblastoma-derived cell lines. All but 1 mutation in the primary samples (12 of 13) were found in stage 3 or 4 of the disease and were harbored in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wildtype kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumors in nude mice. Furthermore, <a href="#3" class="mim-tip-reference" title="Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S. <strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong> Nature 455: 971-974, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923524</a>] [<a href="https://doi.org/10.1038/nature07399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923524">Chen et al. (2008)</a> demonstrated that downregulation of ALK through RNA interference suppressed proliferation of neuroblastoma cells harboring mutated ALK. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others. <strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong> Nature 455: 975-978, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18923525[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/nature07397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923525">George et al. (2008)</a> reported the detection of mutations in the ALK gene (see, e.g., <a href="#0001">105590.0001</a> and <a href="#0004">105590.0004</a>) in 8% of primary neuroblastomas. Five were identified in the kinase domain of ALK, of which 3 were somatic and 2 were germline. The most frequent mutation, F1174L, was identified in 3 different neuroblastoma cell lines as well as in several tumor samples. It was not identified in any germline cases, consistent with it being a somatic mutation. ALK cDNAs encoding the F1174L and R1275Q (<a href="#0001">105590.0001</a>) variants, but not wildtype ALK cDNA, transformed interleukin-3 (IL3; <a href="/entry/147740">147740</a>)-dependent murine hematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to a small-molecule inhibitor of ALK. Furthermore, 2 human neuroblastoma cell lines harboring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis. Short hairpin RNA-mediated knockdown of ALK expression also resulted in apoptosis and impaired cell proliferation. Thus, <a href="#8" class="mim-tip-reference" title="George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others. <strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong> Nature 455: 975-978, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18923525[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/nature07397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923525">George et al. (2008)</a> concluded that activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumors and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923525" 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="#16" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. <strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong> Nature 455: 930-935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[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/nature07261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724359">Mosse et al. (2008)</a>, <a href="#9" class="mim-tip-reference" title="Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O. <strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong> Nature 455: 967-970, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923523</a>] [<a href="https://doi.org/10.1038/nature07398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923523">Janoueix-Lerosey et al. (2008)</a>, <a href="#3" class="mim-tip-reference" title="Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S. <strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong> Nature 455: 971-974, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923524</a>] [<a href="https://doi.org/10.1038/nature07399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923524">Chen et al. (2008)</a>, and <a href="#8" class="mim-tip-reference" title="George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others. <strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong> Nature 455: 975-978, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18923525[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/nature07397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923525">George et al. (2008)</a> all found somatic missense mutations at codon F1174, within the kinase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18923525+18923523+18724359+18923524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine the frequency of ALK mutations in neuroblastic tumors, <a href="#2" class="mim-tip-reference" title="Bourdeaut, F., Ferrand, S., Brugieres, L., Hilbert, M., Ribeiro, A., Lacroix, L., Benard, J., Combaret, V., Michon, J., Valteau-Couanet, D., Isidor, B., Rialland, X., and 8 others. <strong>ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.</strong> Europ. J. Hum. Genet. 20: 291-297, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22071890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22071890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22071890[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/ejhg.2011.195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22071890">Bourdeaut et al. (2012)</a> sequenced the ALK gene in 26 patients with perinatal onset of neuroblastoma, 16 patients with multifocal postnatal onset of neuroblastoma, and 8 children or young adults with multiple malignancies, including a neuroblastic tumor. A de novo heterozygous germline mutation (R1275Q; <a href="#0001">105590.0001</a>) was found in 1 patient with perinatal onset, and 2 different heterozygous mutations (see, e.g., <a href="#0003">105590.0003</a>) were found in 2 unrelated patients with postnatal multifocal onset. However, each of the latter 2 mutations were found in several unaffected relatives, indicating incomplete penetrance. Tumor tissue from all 3 patients also carried the corresponding mutation. Considering the whole cohort, younger age at onset did not seem to offer selection criteria for ALK analysis, but all mutation carriers had multifocal tumors. <a href="#2" class="mim-tip-reference" title="Bourdeaut, F., Ferrand, S., Brugieres, L., Hilbert, M., Ribeiro, A., Lacroix, L., Benard, J., Combaret, V., Michon, J., Valteau-Couanet, D., Isidor, B., Rialland, X., and 8 others. <strong>ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.</strong> Europ. J. Hum. Genet. 20: 291-297, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22071890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22071890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22071890[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/ejhg.2011.195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22071890">Bourdeaut et al. (2012)</a> concluded that ALK mutations are rare events in patients with a high probability of predisposition to neuroblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22071890" 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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In an 8-year-old Brazilian girl and her 27-year-old mother with severe gingival fibromatosis (see GINGF3, <a href="/entry/609955">609955</a>), and her mildly affected 64-year-old maternal grandmother (family A), <a href="#11" class="mim-tip-reference" title="Machado, R. A., de Andrade, R. S., Pego, S. P. B., Krepischi, A. C. V., Coletta, R. D., Martelli-Junior, H. <strong>New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes.</strong> J. Periodont. 94: 108-118, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35665929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35665929</a>] [<a href="https://doi.org/10.1002/JPER.22-0219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35665929">Machado et al. (2023)</a> identified heterozygosity for a c.361C-T transition in the ALK gene, resulting in an arg121-to-trp (R121W) substitution at a nonconserved residue located between functional domains. The variant was not found in the proband's unaffected father or in an unaffected maternal uncle. The authors noted that in a German family with gingival fibromatosis mapping to chromosome 2p23, no mutation had been found in the ALK gene (<a href="#17" class="mim-tip-reference" title="Pampel, M., Maier, S., Kreczy, A., Weirich-Schwaiger, H., Utermann, G., Janecke, A. R. <strong>Refinement of the GINGF3 locus for hereditary gingival fibromatosis.</strong> Europ. J. Pediat. 169: 327-332, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19633868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19633868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19633868[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/10.1007/s00431-009-1034-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19633868">Pampel et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=35665929+19633868" 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="#4" class="mim-tip-reference" title="Chiarle, R., Martinengo, C., Mastini, C., Ambrogio, C., D'Escamard, V., Forni, G., Inghirami, G. <strong>The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination.</strong> Nature Med. 14: 676-680, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469826</a>] [<a href="https://doi.org/10.1038/nm1769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469826">Chiarle et al. (2008)</a> vaccinated BALB/c mice with DNA plasmids encoding portions of the cytoplasmic domain of ALK and observed potent and long-lasting protection from local and systemic lymphoma growth. The vaccination elicited ALK-specific interferon-gamma (<a href="/entry/147570">147570</a>) responses and CD8+ T cell-mediated cytotoxicity. A combination of chemotherapy and vaccination significantly enhanced the survival of mice challenged with ALK+ lymphomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469826" 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>EML4-ALK Fusion Gene</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Maddalo, D., Manchado, E., Concepcion, C. P., Bonetti, C., Vidigal, J. A., Han, Y.-C., Ogrodowski, P., Crippa, A., Rekhtman, N., de Stanchina, E., Lowe, S. W., Ventura, A. <strong>In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system.</strong> Nature 516: 423-427, 2014. Note: Erratum: Nature 524: 502 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25337876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25337876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25337876[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/nature13902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25337876">Maddalo et al. (2014)</a> described an efficient method to induce specific chromosomal rearrangements in vivo using viral-mediated delivery of the CRISPR/Cas9 system to somatic cells of adult animals, applying it to generate a mouse model of EML4 (<a href="/entry/607442">607442</a>)-ALK-driven lung cancer. The resulting tumors invariably harbored the Eml4-Alk inversion; expressed the Eml4-Alk fusion gene; displayed histopathologic and molecular features typical of ALK-positive human nonsmall cell lung cancers (NSCLCs); and responded to treatment with ALK inhibitors. <a href="#12" class="mim-tip-reference" title="Maddalo, D., Manchado, E., Concepcion, C. P., Bonetti, C., Vidigal, J. A., Han, Y.-C., Ogrodowski, P., Crippa, A., Rekhtman, N., de Stanchina, E., Lowe, S. W., Ventura, A. <strong>In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system.</strong> Nature 516: 423-427, 2014. Note: Erratum: Nature 524: 502 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25337876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25337876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25337876[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/nature13902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25337876">Maddalo et al. (2014)</a> suggested that this general strategy substantially expands the ability to model human cancers in mice and potentially in other organisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25337876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=105590[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">rs113994087 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994087;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=rs113994087" 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=rs113994087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 5 independent families segregating neuroblastoma (NBLST3; <a href="/entry/613014">613014</a>), <a href="#16" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. <strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong> Nature 455: 930-935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[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/nature07261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724359">Mosse et al. (2008)</a> identified a 3824G-A transition in the ALK gene, resulting in an arg1275-to-gln (R1275Q) substitution. The mutation manifested incomplete penetrance but was not identified in 218 normal control chromosomes. The mutation occurs in the kinase activation loop of the protein and has a 91% probability of being an activating mutation. In 1 family an unaffected mutation-carrying mother transmitted the mutation to 3 offspring by 3 different fathers; each of these 3 offspring developed neuroblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18724359" 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="Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O. <strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong> Nature 455: 967-970, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923523</a>] [<a href="https://doi.org/10.1038/nature07398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923523">Janoueix-Lerosey et al. (2008)</a> identified 1 family in which an unaffected mutation-carrying mother transmitted the mutation to 2 affected offspring, each by a different father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others. <strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong> Nature 455: 975-978, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18923525[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/nature07397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923525">George et al. (2008)</a> identified this mutation in a patient with neuroblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923525" 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="Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S. <strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong> Nature 455: 971-974, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923524</a>] [<a href="https://doi.org/10.1038/nature07399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923524">Chen et al. (2008)</a> identified the R1275Q substitution as a somatic mutation in several neuroblastoma tumor samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bourdeaut, F., Ferrand, S., Brugieres, L., Hilbert, M., Ribeiro, A., Lacroix, L., Benard, J., Combaret, V., Michon, J., Valteau-Couanet, D., Isidor, B., Rialland, X., and 8 others. <strong>ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.</strong> Europ. J. Hum. Genet. 20: 291-297, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22071890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22071890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22071890[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/ejhg.2011.195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22071890">Bourdeaut et al. (2012)</a> identified a de novo heterozygous germline R1275Q mutation in a patient with perinatal onset of multifocal neuroblastoma. The mutation was also found in several tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22071890" 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">rs113994088 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994088;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=rs113994088" 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=rs113994088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a large 3-generation pedigree segregating familial neuroblastoma (NBLST3; <a href="/entry/613014">613014</a>), <a href="#16" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. <strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong> Nature 455: 930-935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[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/nature07261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724359">Mosse et al. (2008)</a> identified a G-to-C transversion at nucleotide 3383 in the ALK gene, resulting in a glycine-to-alanine substitution at codon 1128 (G1128A). Five individuals with the mutation developed neuroblastoma, but several carriers did not, indicating incomplete penetrance. This mutation occurred in the P loop of the protein and was considered to have 95% probability of being an activating mutation. This mutation was not identified in 218 normal control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18724359" 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">rs113994089 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994089;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=rs113994089" 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=rs113994089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 families segregating neuroblastoma (NBLST3; <a href="/entry/613014">613014</a>), <a href="#16" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. <strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong> Nature 455: 930-935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[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/nature07261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724359">Mosse et al. (2008)</a> identified a G-to-C transversion at nucleotide 3575 of the ALK gene, resulting in an arginine-to-proline substitution at codon 1192 (R1192P). This mutation manifested incomplete penetrance. The mutation occurred in the beta-4 strand of the protein and was predicted with 96% probability to be an activating mutation. The mutation was not identified in 218 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18724359" 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="Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O. <strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong> Nature 455: 967-970, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923523</a>] [<a href="https://doi.org/10.1038/nature07398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923523">Janoueix-Lerosey et al. (2008)</a> independently identified a family segregating neuroblastoma and carrying the R1192P allele. In this 3-generation pedigree, the grandmother was unaffected. The daughter developed a ganglioneuroblastoma at 12 years of age, and 2 grandchildren developed stage 4 neuroblastomas at 3 and 4 months of age, respectively. In addition to the grandmother, the parents of the affected grandchildren were also unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bourdeaut, F., Ferrand, S., Brugieres, L., Hilbert, M., Ribeiro, A., Lacroix, L., Benard, J., Combaret, V., Michon, J., Valteau-Couanet, D., Isidor, B., Rialland, X., and 8 others. <strong>ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.</strong> Europ. J. Hum. Genet. 20: 291-297, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22071890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22071890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22071890[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/ejhg.2011.195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22071890">Bourdeaut et al. (2012)</a> identified a heterozygous germline R1192P mutation in a child who developed neuroblastoma at age 6 months and later developed multiple ganglioneuromas in various places up to age 6 years. The mutation was found in all tumors tested. However, this germline mutation was also found in 3 unaffected family members, including the patient's mother, indicating incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22071890" 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 NEUROBLASTOMA, SUSCEPTIBILITY TO, 3</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> rs113994091 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994091;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/rs113994091?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=rs113994091" 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=rs113994091" 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=RCV000019712 OR RCV001020341 OR RCV004589517" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019712, RCV001020341, RCV004589517" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019712...</a>
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<p>In a patient with neuroblastoma (NBLST3; <a href="/entry/613014">613014</a>), <a href="#8" class="mim-tip-reference" title="George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others. <strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong> Nature 455: 975-978, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18923525[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/nature07397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923525">George et al. (2008)</a> identified a 3452C-T transition in the ALK gene, resulting in a threonine-to-methionine substitution at codon 1151 (T1151M) in the kinase domain of ALK. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923525" 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>REFERENCES</strong>
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<a id="Benharroch1998" class="mim-anchor"></a>
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Benharroch, D., Meguerian-Bedoyan, Z., Lamant, L., Amin, C., Brugieres, L., Terrier-Lacombe, M.-J., Haralambieva, E., Pulford, K., Pileri, S., Morris, S. W., Mason, D. Y., Delsol, G.
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<strong>ALK-positive lymphoma: a single disease with a broad spectrum of morphology.</strong>
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Blood 91: 2076-2084, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490693</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9490693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Bourdeaut2012" class="mim-anchor"></a>
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Bourdeaut, F., Ferrand, S., Brugieres, L., Hilbert, M., Ribeiro, A., Lacroix, L., Benard, J., Combaret, V., Michon, J., Valteau-Couanet, D., Isidor, B., Rialland, X., and 8 others.
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<strong>ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.</strong>
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Europ. J. Hum. Genet. 20: 291-297, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22071890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22071890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22071890[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=22071890" 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/ejhg.2011.195" target="_blank">Full Text</a>]
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<a id="Chen2008" class="mim-anchor"></a>
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Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S.
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<strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong>
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Nature 455: 971-974, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923524</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923524" 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/nature07399" target="_blank">Full Text</a>]
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Chiarle, R., Martinengo, C., Mastini, C., Ambrogio, C., D'Escamard, V., Forni, G., Inghirami, G.
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<strong>The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination.</strong>
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Nature Med. 14: 676-680, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469826</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469826" 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/nm1769" target="_blank">Full Text</a>]
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<a id="Choi2010" class="mim-anchor"></a>
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Choi, Y. L., Soda, M., Yamashita, Y., Ueno, T., Takashima, J., Nakajima, T., Yatabe, Y., Takeuchi, K., Hamada, T., Haruta, H., Ishikawa, Y., Kimura, H., Mitsudomi, T., Tanio, Y., Mano, H.
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<strong>EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.</strong>
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New Eng. J. Med. 363: 1734-1739, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20979473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20979473</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20979473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1007478" target="_blank">Full Text</a>]
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Cools, J., Wlodarska, I., Somers, R., Mentens, N., Pedeutour, F., Maes, B., De Wolf-Peeters, C., Pauwels, P., Hagemeijer, A., Marynen, P.
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<strong>Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor.</strong>
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Genes Chromosomes Cancer 34: 354-362, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112524</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112524" 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/gcc.10033" target="_blank">Full Text</a>]
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Englund, C., Loren, C. E., Grabbe, C., Varshney, G. K., Deleuil, F., Hallberg, B., Palmer, R. H.
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<strong>Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion.</strong>
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Nature 425: 512-516, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14523447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14523447</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14523447" 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/nature01950" target="_blank">Full Text</a>]
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<a id="George2008" class="mim-anchor"></a>
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George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others.
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<strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong>
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Nature 455: 975-978, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18923525[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=18923525" 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/nature07397" target="_blank">Full Text</a>]
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<a id="Janoueix-Lerosey2008" class="mim-anchor"></a>
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<div class="">
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Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O.
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<strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong>
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Nature 455: 967-970, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923523</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923523" 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/nature07398" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nm1659" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 10/31/2024
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Bao Lige - updated : 12/12/2022<br>Patricia A. Hartz - updated : 01/27/2017<br>Ada Hamosh - updated : 11/20/2015<br>Ada Hamosh - updated : 6/2/2015<br>Cassandra L. Kniffin - updated : 11/5/2012<br>Paul J. Converse - updated : 10/31/2011<br>Patricia A. Hartz - updated : 2/17/2011<br>Ada Hamosh - updated : 1/3/2011<br>Ada Hamosh - updated : 11/17/2008<br>Marla J. F. O'Neill - updated : 6/26/2008<br>Paul J. Converse - updated : 2/4/2008<br>Ada Hamosh - updated : 8/13/2007<br>Patricia A. Hartz - updated : 1/25/2007<br>Ada Hamosh - updated : 10/29/2003<br>Victor A. McKusick - updated : 4/30/1998
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 6/21/1994
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 10/31/2024
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alopez : 10/18/2024<br>carol : 12/14/2022<br>alopez : 12/13/2022<br>mgross : 12/12/2022<br>mgross : 01/27/2017<br>carol : 03/28/2016<br>alopez : 11/20/2015<br>alopez : 10/19/2015<br>alopez : 6/2/2015<br>carol : 11/8/2012<br>ckniffin : 11/5/2012<br>carol : 10/16/2012<br>terry : 11/4/2011<br>mgross : 11/2/2011<br>terry : 10/31/2011<br>mgross : 2/23/2011<br>terry : 2/17/2011<br>alopez : 1/6/2011<br>terry : 1/3/2011<br>carol : 9/21/2009<br>ckniffin : 9/18/2009<br>alopez : 12/5/2008<br>terry : 11/17/2008<br>alopez : 6/30/2008<br>terry : 6/26/2008<br>carol : 3/25/2008<br>mgross : 2/4/2008<br>carol : 8/14/2007<br>carol : 8/14/2007<br>terry : 8/13/2007<br>mgross : 1/25/2007<br>alopez : 10/30/2003<br>terry : 10/29/2003<br>carol : 5/4/1998<br>terry : 4/30/1998<br>mark : 7/11/1995<br>jason : 6/21/1994
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<span class="mim-font">
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<strong>*</strong> 105590
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ALK RECEPTOR TYROSINE KINASE; ALK
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<em>Alternative titles; symbols</em>
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ANAPLASTIC LYMPHOMA KINASE
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Other entities represented in this entry:
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ALK/EML4 FUSION GENE, INCLUDED
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ALK/NPM1 FUSION GENE, INCLUDED<br />
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ALK/RNF213 FUSION GENE, INCLUDED<br />
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ALK/CARS FUSION GENE, INCLUDED<br />
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ALK/CLTC FUSION GENE, INCLUDED
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ALK</em></strong>
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Cytogenetic location: 2p23.2-p23.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:29,192,774-29,921,586 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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2p23.2-p23.1
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{Neuroblastoma, susceptibility to, 3}
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<span class="mim-font">
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613014
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The ALK gene encodes a receptor tyrosine kinase that plays a role in regulation of Wnt/beta-catenin (see 116806) signaling and is involved in the development of many cancer types, especially non-small-cell lung cancer (NSCLC) (summary by Majumder et al., 2021). </p>
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<strong>Cloning and Expression</strong>
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<p>Large-cell lymphomas comprise approximately 25% of all non-Hodgkin lymphomas in children and young adults, and approximately one-third of these tumors have a t(2;5)(p23;q35) translocation. By a positional cloning strategy, Morris et al. (1994) demonstrated that the rearrangement fused the nucleophosmin gene (NPM1; 164040), located on 5q35, to a previously unidentified protein tyrosine kinase gene, which they called anaplastic lymphoma kinase (ALK), located on 2p23. In the predicted hybrid protein, the amino terminus of nucleophosmin is linked to the catalytic domain of ALK. Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases (see INSR; 147670). Unscheduled expression of the truncated ALK was thought to contribute to malignant transformation in these lymphomas. </p>
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<strong>Gene Function</strong>
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<p>Benharroch et al. (1998) studied the morphologic and phenotypic spectrum of 123 cases of lymphoma, all of which expressed ALK protein. They provided strong evidence that the morphologic patterns of anaplastic large-cell lymphoma (ALCL), described in previous reports as representing possible subtypes of ALCL, are in fact morphologic variants of the same disease entity. They concluded that ALK-positive neoplasms represent a distinct entity. Because the morphology of the tumors is often neither anaplastic nor large cell, the authors suggested that the tumors should be referred to as ALK lymphomas. </p><p>The secreted protein 'Jelly belly' (Jeb) is required for an essential signaling event in Drosophila muscle development. In the absence of functional Jeb, visceral muscle precursors are normally specified but fail to migrate and differentiate. Lee et al. (2003) demonstrated that the Jeb receptor is the Drosophila homolog of ALK. In Drosophila, localized Jeb activates Alk and the downstream Ras/mitogen-activated protein kinase cascade to specify a select group of visceral muscle precursors as muscle-patterning pioneers. Jeb/Alk signaling induces the myoblast fusion gene 'dumbfounded' (duf; also known as kirre; see 607761) as well as org1, a Drosophila homolog of mammalian TBX1 (602054), in these cells. </p><p>Englund et al. (2003) also showed that Drosophila Alk is the receptor for Jeb in the developing visceral mesoderm and that Jeb binding stimulates an Alk-driven extracellular signal-regulated kinase-mediated signaling pathway, which results in the expression of the downstream gene duf, which is needed for muscle fusion. This new signal transduction pathway drives specification of the muscle founder cells, and the regulation of duf expression by Drosophila Alk/RTK explains the visceral-mesoderm-specific muscle fusion defects observed in both Alk and Jeb mutant animals. </p><p>By expression profiling of ALK-positive ALCLs, Piva et al. (2006) identified a large group of ALK-regulated genes. Functional RNA interference screening on a set of these transcriptional targets revealed that CEBPB (189965) and BCL2A1 (601056) were absolutely necessary to induce cell transformation and/or to sustain growth and survival of ALK-positive ALCL cells. </p><p>IL22R1 (605457) is not expressed on normal leukocytes, but it is expressed on T-cells from ALK-positive ALCL patients. Savan et al. (2011) found that mice expressing a human IL22R1 transgene on lymphocytes exhibited deterioration of health at 8 to 12 weeks of age and death due to multiorgan inflammation. Transgenic mice developed neutrophilia that correlated with increased circulating Il17 (IL17A; 603149) and Gcsf (CSF3; 138970), as well as increased serum Il22 (605330). ALK-positive ALCL patients had elevated IL22, IL17, and IL8 (146930) before treatment, but those in complete remission after chemotherapy did not have detectable IL22 and IL17. Savan et al. (2011) concluded that IL22R1 and IL22 are involved in inflammation and ALK-positive ALCL. </p><p>By reciprocal immunoprecipitation of transfected 293T cells, Takagi et al. (2013) found that the adaptor protein SHF (617313) interacted with ALK. In neuroblastoma cells and patient tissue, ALK and SHF showed an inverse relationship, with high ALK and low SHF mRNA associated with poor prognosis. Overexpression of ALK and knockdown of SHF via short interfering RNA yielded similar and additive results, including increased growth, ALK phosphorylation, and activation of ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and STAT3 (102582). Knockdown of SHF also increased mobility and invasiveness of neuroblastoma cells. Takagi et al. (2013) concluded that SHF negatively regulates ALK signal transduction. </p><p>Wiesner et al. (2015) reported a novel isoform of ALK that is expressed in approximately 11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19 and is termed ALK(ATI). In ALK(ATI)-expressing tumors, the ATI site is enriched for H3K4 trimethylation and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes 3 proteins with molecular masses of 61.1, 60.8, and 58.7 kD, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signaling pathways, drives growth factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumors may benefit from ALK inhibitors. </p><p>By Western blot analysis, Majumder et al. (2021) showed that levels of GRB2 (108355) and NOX4 (605261) were elevated in tissues from mouse models for Alzheimer disease (AD; see 104300) and type 2 diabetes (T2D; 125853), as well as in tissues from AD and T2D patients. Knockdown analysis in SHSY-5Y and HepG2 cells revealed that miRNA1271 targeted and restricted expression of ALK and RYK (600524), which elevated expression of GRB2 and NOX4. Moreover, PAX4 (167413), a transcription factor for both GRB2 and NOX4, was overexpressed during ALK and RYK knockdown due to reduced expression of the PAX4 suppressor ARX (300382) via beta-catenin (see 116806) signaling. In addition, expression of various cytoskeletal proteins was downregulated in liver tissue of T2D patients and in ALK/RYK knockdown cells, but overexpression of GRB2 reversed the cytoskeletal degradation through interaction with NOX4. </p><p><strong><em>ALK/EML4 Fusion Protein</em></strong></p><p>
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Soda et al. (2007) showed that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the EML4 gene (607442) and the ALK gene in non-small-cell lung cancer (211980) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumors in nude mice. Soda et al. (2007) detected the ALK-EML4 fusion transcript in 5 of 75 (6.7%) Japanese patients with non-small-cell lung cancer patients examined; none of these patients had a mutation in the epidermal growth factor receptor gene (EGFR; 131550). The fusion gene encoded a deduced 1,059-amino acid protein with an N-terminal portion (residues 1-496) identical to that of human EML4 and a C-terminal portion (residues 497-1059) identical to the intracellular domain (residues 1058-1620) of human ALK. </p><p>The EML4-ALK fusion type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers. Choi et al. (2010) reported the discovery of 2 secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to 2 different ALK inhibitors. </p><p><strong><em>ALK/NPM1 Fusion Protein</em></strong></p><p>
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Zhang et al. (2007) stated that ALK tyrosine kinase expression is normally confined to neural cells, but chromosomal translocations involving ALK and various partners, most frequently NPM1, result in ectopic expression of ALK in a subset of T-cell lymphomas (TCLs). The NPM1/ALK fusion protein contains the NPM1 oligomerization motif and the ALK catalytic domain, is constitutively activated through autophosphorylation, and mediates malignant cell transformation in vitro and in vivo by activating downstream effectors, including STAT3 (102582). Zhang et al. (2007) found that TCL cell lines expressing NPM1/ALK expressed STAT5B (604260), but not STAT5A (601511), protein, whereas normal resting and activated T cells from peripheral blood and ALK-negative TCL cell lines expressed STAT5A protein. Activated NPM1/ALK-positive TCL cell lines also did not express STAT5A mRNA, in spite of having an intact STAT5A gene. Analysis of the CpG island in the STAT5A promoter showed that the region was methylated in NPM1/ALK-positive, but not NPM1/ALK-negative, T cells. Chromatin immunoprecipitation analysis revealed that SP1 (189906) bound the STAT5A promoter in normal activated T cells, whereas MECP2 (300005) bound the promoter of NPM1/ALK-positive TCL cells. Demethylation of the promoter resulted in STAT5A activation and inhibition of NPM1/ALK expression by binding of STAT5A to the NPM1/ALK fusion gene. Expression of NPM1/ALK in NPM1/ALK-negative TCL cells resulted in silencing of STAT5A in a STAT3-dependent manner, whereas small interfering RNA mediated-depletion of NPM1/ALK resulted in STAT5A expression. Zhang et al. (2007) concluded that NPM1/ALK induces epigenetic silencing of the STAT5A gene and that the STAT5A protein can act as a tumor suppressor by inhibiting NPM1/ALK expression. </p>
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</span>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Mosse et al. (2008) stated that the ALK gene comprises 29 coding exons. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Morris et al. (1994) identified the ALK gene on chromosome 2p23 by positional cloning using a t(2;5)(p23;q35) translocation. Mathew et al. (1995) mapped the mouse homolog to chromosome 17 by interspecific backcross analysis, thus confirming the homology between the portion of distal mouse 17 and the short arm of human chromosome 2. </p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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<p>In 2 patients with ALK-positive anaplastic large-cell lymphoma (ALCL) and a third patient with ALK-negative inflammatory myofibroblastic tumors (IMT), Cools et al. (2002) identified novel rearrangements involving the ALK gene. One ALCL patient had a t(2;17)(p23;q25) that resulted in fusion of exons of the ALO17 gene (RNF213; 613768) to exons of the ALK gene. The other ALCL patient had an unknown karyotype that led to fusion of exons of the CLTC gene (118955) to exons of the ALK gene. The IMT patient had a t(2;11;2)(p23;p15;q31) that resulted in fusion of exons of the CARS gene (123859) to exons of the ALK gene. The predicted fusion proteins contain 1,172 N-terminal amino acids of ALO17, 1,634 N-terminal amino acids of CLTC, or 606 N-terminal amino acids of CARS fused in frame to the same 562 amino acids of ALK, including the ALK kinase domain. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Susceptibility to Neuroblastoma</em></strong></p><p>
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Mosse et al. (2008) identified 3 separate germline missense mutations in the tyrosine kinase domain of the ALK gene (105590.0001-105590.0003) that segregated with the disease in 8 separate families with neuroblastoma (NBLST3; 613014). There was incomplete penetrance. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of the samples. Nine of the 10 mutations mapped to critical regions of the kinase domain and were predicted with high probability to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK mRNA resulted in profound inhibition of growth in all cell lines harboring mutant or amplified ALK, as well as in 2 of 6 wildtype cell lines for ALK. Mosse et al. (2008) concluded that heritable mutations of ALK are the main cause of susceptibility to the development of neuroblastoma within families. </p><p>Janoueix-Lerosey et al. (2008) conducted a genomewide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the ALK tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumor DNAs, they identified somatic mutations of the ALK kinase domain that mainly clustered in 2 hotspots. Germline mutations were observed in 2 neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated, and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wildtype ALK, led to a marked decrease of cell proliferation. Altogether, Janoueix-Lerosey et al. (2008) concluded that their data identified ALK as critical player in neuroblastoma development that may represent a therapeutic target. </p><p>In a genomewide scan of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, Chen et al. (2008) identified the ALK locus as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed 8 novel missense mutations in 13 of 215 (6.1%) fresh tumors and 8 of 24 (33%) neuroblastoma-derived cell lines. All but 1 mutation in the primary samples (12 of 13) were found in stage 3 or 4 of the disease and were harbored in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wildtype kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumors in nude mice. Furthermore, Chen et al. (2008) demonstrated that downregulation of ALK through RNA interference suppressed proliferation of neuroblastoma cells harboring mutated ALK. </p><p>George et al. (2008) reported the detection of mutations in the ALK gene (see, e.g., 105590.0001 and 105590.0004) in 8% of primary neuroblastomas. Five were identified in the kinase domain of ALK, of which 3 were somatic and 2 were germline. The most frequent mutation, F1174L, was identified in 3 different neuroblastoma cell lines as well as in several tumor samples. It was not identified in any germline cases, consistent with it being a somatic mutation. ALK cDNAs encoding the F1174L and R1275Q (105590.0001) variants, but not wildtype ALK cDNA, transformed interleukin-3 (IL3; 147740)-dependent murine hematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to a small-molecule inhibitor of ALK. Furthermore, 2 human neuroblastoma cell lines harboring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis. Short hairpin RNA-mediated knockdown of ALK expression also resulted in apoptosis and impaired cell proliferation. Thus, George et al. (2008) concluded that activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumors and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibitors. </p><p>Mosse et al. (2008), Janoueix-Lerosey et al. (2008), Chen et al. (2008), and George et al. (2008) all found somatic missense mutations at codon F1174, within the kinase domain. </p><p>To determine the frequency of ALK mutations in neuroblastic tumors, Bourdeaut et al. (2012) sequenced the ALK gene in 26 patients with perinatal onset of neuroblastoma, 16 patients with multifocal postnatal onset of neuroblastoma, and 8 children or young adults with multiple malignancies, including a neuroblastic tumor. A de novo heterozygous germline mutation (R1275Q; 105590.0001) was found in 1 patient with perinatal onset, and 2 different heterozygous mutations (see, e.g., 105590.0003) were found in 2 unrelated patients with postnatal multifocal onset. However, each of the latter 2 mutations were found in several unaffected relatives, indicating incomplete penetrance. Tumor tissue from all 3 patients also carried the corresponding mutation. Considering the whole cohort, younger age at onset did not seem to offer selection criteria for ALK analysis, but all mutation carriers had multifocal tumors. Bourdeaut et al. (2012) concluded that ALK mutations are rare events in patients with a high probability of predisposition to neuroblastoma. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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In an 8-year-old Brazilian girl and her 27-year-old mother with severe gingival fibromatosis (see GINGF3, 609955), and her mildly affected 64-year-old maternal grandmother (family A), Machado et al. (2023) identified heterozygosity for a c.361C-T transition in the ALK gene, resulting in an arg121-to-trp (R121W) substitution at a nonconserved residue located between functional domains. The variant was not found in the proband's unaffected father or in an unaffected maternal uncle. The authors noted that in a German family with gingival fibromatosis mapping to chromosome 2p23, no mutation had been found in the ALK gene (Pampel et al., 2010). </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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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Chiarle et al. (2008) vaccinated BALB/c mice with DNA plasmids encoding portions of the cytoplasmic domain of ALK and observed potent and long-lasting protection from local and systemic lymphoma growth. The vaccination elicited ALK-specific interferon-gamma (147570) responses and CD8+ T cell-mediated cytotoxicity. A combination of chemotherapy and vaccination significantly enhanced the survival of mice challenged with ALK+ lymphomas. </p><p><strong><em>EML4-ALK Fusion Gene</em></strong></p><p>
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Maddalo et al. (2014) described an efficient method to induce specific chromosomal rearrangements in vivo using viral-mediated delivery of the CRISPR/Cas9 system to somatic cells of adult animals, applying it to generate a mouse model of EML4 (607442)-ALK-driven lung cancer. The resulting tumors invariably harbored the Eml4-Alk inversion; expressed the Eml4-Alk fusion gene; displayed histopathologic and molecular features typical of ALK-positive human nonsmall cell lung cancers (NSCLCs); and responded to treatment with ALK inhibitors. Maddalo et al. (2014) suggested that this general strategy substantially expands the ability to model human cancers in mice and potentially in other organisms. </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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<h4>
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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>4 Selected Examples):</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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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 NEUROBLASTOMA, SUSCEPTIBILITY TO, 3</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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ALK, ARG1275GLN
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<br />
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SNP: rs113994087,
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ClinVar: RCV000019709, RCV001268655, RCV002354167
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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 5 independent families segregating neuroblastoma (NBLST3; 613014), Mosse et al. (2008) identified a 3824G-A transition in the ALK gene, resulting in an arg1275-to-gln (R1275Q) substitution. The mutation manifested incomplete penetrance but was not identified in 218 normal control chromosomes. The mutation occurs in the kinase activation loop of the protein and has a 91% probability of being an activating mutation. In 1 family an unaffected mutation-carrying mother transmitted the mutation to 3 offspring by 3 different fathers; each of these 3 offspring developed neuroblastoma. </p><p>Janoueix-Lerosey et al. (2008) identified 1 family in which an unaffected mutation-carrying mother transmitted the mutation to 2 affected offspring, each by a different father. </p><p>George et al. (2008) identified this mutation in a patient with neuroblastoma. </p><p>Chen et al. (2008) identified the R1275Q substitution as a somatic mutation in several neuroblastoma tumor samples. </p><p>Bourdeaut et al. (2012) identified a de novo heterozygous germline R1275Q mutation in a patient with perinatal onset of multifocal neuroblastoma. The mutation was also found in several tumors. </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>.0002 NEUROBLASTOMA, SUSCEPTIBILITY TO, 3</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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ALK, GLY1128ALA
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<br />
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SNP: rs113994088,
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ClinVar: RCV000019710
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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 large 3-generation pedigree segregating familial neuroblastoma (NBLST3; 613014), Mosse et al. (2008) identified a G-to-C transversion at nucleotide 3383 in the ALK gene, resulting in a glycine-to-alanine substitution at codon 1128 (G1128A). Five individuals with the mutation developed neuroblastoma, but several carriers did not, indicating incomplete penetrance. This mutation occurred in the P loop of the protein and was considered to have 95% probability of being an activating mutation. This mutation was not identified in 218 normal control alleles. </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>.0003 NEUROBLASTOMA, SUSCEPTIBILITY TO, 3</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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ALK, ARG1192PRO
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<br />
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SNP: rs113994089,
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ClinVar: RCV000019711
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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 families segregating neuroblastoma (NBLST3; 613014), Mosse et al. (2008) identified a G-to-C transversion at nucleotide 3575 of the ALK gene, resulting in an arginine-to-proline substitution at codon 1192 (R1192P). This mutation manifested incomplete penetrance. The mutation occurred in the beta-4 strand of the protein and was predicted with 96% probability to be an activating mutation. The mutation was not identified in 218 control chromosomes. </p><p>Janoueix-Lerosey et al. (2008) independently identified a family segregating neuroblastoma and carrying the R1192P allele. In this 3-generation pedigree, the grandmother was unaffected. The daughter developed a ganglioneuroblastoma at 12 years of age, and 2 grandchildren developed stage 4 neuroblastomas at 3 and 4 months of age, respectively. In addition to the grandmother, the parents of the affected grandchildren were also unaffected. </p><p>Bourdeaut et al. (2012) identified a heterozygous germline R1192P mutation in a child who developed neuroblastoma at age 6 months and later developed multiple ganglioneuromas in various places up to age 6 years. The mutation was found in all tumors tested. However, this germline mutation was also found in 3 unaffected family members, including the patient's mother, indicating incomplete penetrance. </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>
|
|
<span class="mim-font">
|
|
<strong>.0004 NEUROBLASTOMA, SUSCEPTIBILITY TO, 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
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<span class="mim-text-font">
|
|
|
|
ALK, THR1151MET
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|
|
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<br />
|
|
|
|
SNP: rs113994091,
|
|
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|
|
|
gnomAD: rs113994091,
|
|
|
|
|
|
ClinVar: RCV000019712, RCV001020341, RCV004589517
|
|
|
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|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with neuroblastoma (NBLST3; 613014), George et al. (2008) identified a 3452C-T transition in the ALK gene, resulting in a threonine-to-methionine substitution at codon 1151 (T1151M) in the kinase domain of ALK. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
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<div>
|
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<p />
|
|
</div>
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<div>
|
|
<ol>
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<li>
|
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<p class="mim-text-font">
|
|
Benharroch, D., Meguerian-Bedoyan, Z., Lamant, L., Amin, C., Brugieres, L., Terrier-Lacombe, M.-J., Haralambieva, E., Pulford, K., Pileri, S., Morris, S. W., Mason, D. Y., Delsol, G.
|
|
<strong>ALK-positive lymphoma: a single disease with a broad spectrum of morphology.</strong>
|
|
Blood 91: 2076-2084, 1998.
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[PubMed: 9490693]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bourdeaut, F., Ferrand, S., Brugieres, L., Hilbert, M., Ribeiro, A., Lacroix, L., Benard, J., Combaret, V., Michon, J., Valteau-Couanet, D., Isidor, B., Rialland, X., and 8 others.
|
|
<strong>ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.</strong>
|
|
Europ. J. Hum. Genet. 20: 291-297, 2012.
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[PubMed: 22071890]
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[Full Text: https://doi.org/10.1038/ejhg.2011.195]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S.
|
|
<strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong>
|
|
Nature 455: 971-974, 2008.
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[PubMed: 18923524]
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[Full Text: https://doi.org/10.1038/nature07399]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Chiarle, R., Martinengo, C., Mastini, C., Ambrogio, C., D'Escamard, V., Forni, G., Inghirami, G.
|
|
<strong>The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination.</strong>
|
|
Nature Med. 14: 676-680, 2008.
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[PubMed: 18469826]
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[Full Text: https://doi.org/10.1038/nm1769]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Choi, Y. L., Soda, M., Yamashita, Y., Ueno, T., Takashima, J., Nakajima, T., Yatabe, Y., Takeuchi, K., Hamada, T., Haruta, H., Ishikawa, Y., Kimura, H., Mitsudomi, T., Tanio, Y., Mano, H.
|
|
<strong>EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.</strong>
|
|
New Eng. J. Med. 363: 1734-1739, 2010.
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[PubMed: 20979473]
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[Full Text: https://doi.org/10.1056/NEJMoa1007478]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cools, J., Wlodarska, I., Somers, R., Mentens, N., Pedeutour, F., Maes, B., De Wolf-Peeters, C., Pauwels, P., Hagemeijer, A., Marynen, P.
|
|
<strong>Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor.</strong>
|
|
Genes Chromosomes Cancer 34: 354-362, 2002.
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[PubMed: 12112524]
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[Full Text: https://doi.org/10.1002/gcc.10033]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Englund, C., Loren, C. E., Grabbe, C., Varshney, G. K., Deleuil, F., Hallberg, B., Palmer, R. H.
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<strong>Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion.</strong>
|
|
Nature 425: 512-516, 2003.
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[PubMed: 14523447]
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[Full Text: https://doi.org/10.1038/nature01950]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others.
|
|
<strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong>
|
|
Nature 455: 975-978, 2008.
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[PubMed: 18923525]
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[Full Text: https://doi.org/10.1038/nature07397]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O.
|
|
<strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong>
|
|
Nature 455: 967-970, 2008.
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[PubMed: 18923523]
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[Full Text: https://doi.org/10.1038/nature07398]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Lee, H.-H., Norris, A., Weiss, J. B., Frasch, M.
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<strong>Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers.</strong>
|
|
Nature 425: 507-512, 2003.
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[PubMed: 14523446]
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[Full Text: https://doi.org/10.1038/nature01916]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Machado, R. A., de Andrade, R. S., Pego, S. P. B., Krepischi, A. C. V., Coletta, R. D., Martelli-Junior, H.
|
|
<strong>New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes.</strong>
|
|
J. Periodont. 94: 108-118, 2023.
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[PubMed: 35665929]
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[Full Text: https://doi.org/10.1002/JPER.22-0219]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Maddalo, D., Manchado, E., Concepcion, C. P., Bonetti, C., Vidigal, J. A., Han, Y.-C., Ogrodowski, P., Crippa, A., Rekhtman, N., de Stanchina, E., Lowe, S. W., Ventura, A.
|
|
<strong>In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system.</strong>
|
|
Nature 516: 423-427, 2014. Note: Erratum: Nature 524: 502 only, 2015.
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[PubMed: 25337876]
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[Full Text: https://doi.org/10.1038/nature13902]
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</p>
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