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<title>
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Entry
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- #606764 - GASTROINTESTINAL STROMAL TUMOR; GIST
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- OMIM
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<span class="h4">#606764</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/606764"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=(GASTROINTESTINAL STROMAL TUMOR) OR (SDHB OR KIT OR SDHC)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=10584&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/2997" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/gastrointestinal-stromal-tumor" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=44890" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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</a>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:9253" 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="http://www.informatics.jax.org/disease/606764" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA001516/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:9253" 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': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></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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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1187383001, 128755003, 420120006<br />
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<strong>ICD10CM:</strong> C49.A<br />
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<strong>ORPHA:</strong> 44890<br />
|
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<strong>DO:</strong> 9253<br />
|
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
|
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606764
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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GASTROINTESTINAL STROMAL TUMOR; GIST
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/209?start=-3&limit=10&highlight=209">
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1p36.13
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Gastrointestinal stromal tumor
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/606764"> 606764 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Isolated cases">IC</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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SDHB
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/185470"> 185470 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/1349?start=-3&limit=10&highlight=1349">
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1q23.3
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Gastrointestinal stromal tumor
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/606764"> 606764 </a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Isolated cases">IC</abbr>
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
SDHC
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/602413"> 602413 </a>
|
|
</span>
|
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</td>
|
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</tr>
|
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|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/4/226?start=-3&limit=10&highlight=226">
|
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4q12
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Gastrointestinal stromal tumor, familial
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/606764"> 606764 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Isolated cases">IC</abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
KIT
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/164920"> 164920 </a>
|
|
</span>
|
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</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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|
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<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/606764" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
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|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/606764" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/606764" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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|
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<div>
|
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<p />
|
|
</div>
|
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|
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br /> -
|
|
Isolated cases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853237&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853237</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003745" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003745</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003745" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003745</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398241000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398241000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413769002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413769002</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
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</div>
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
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|
|
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Gastrointestinal stromal tumors <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128755003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128755003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/420120006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">420120006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1187383001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1187383001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C49.A" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C49.A</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0238198&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0238198</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100723" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100723</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100723" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100723</a>]</span><br /> -
|
|
Pathology resembles neurofibromas <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675983&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675983</a>]</span><br /> -
|
|
Hyperplasia of the myenteric plexus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675984&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675984</a>]</span><br /> -
|
|
Intestinal obstruction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81060008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81060008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K56.609" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K56.609</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K56.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K56.60</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K56.69" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K56.69</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/560.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">560.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021843&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021843</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005214" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005214</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005214" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005214</a>]</span><br /> -
|
|
Constipation (reported in 1 family with a PDFGRA mutation) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14760008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14760008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/564.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/564.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009806&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009806</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span><br /> -
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Dysphagia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/288939007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">288939007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40739000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40739000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/787.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span><br />
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<span class="h5 mim-font">
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<strong> SKELETAL </strong>
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<div style="margin-left: 2em;">
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<span class="h5 mim-font">
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<em> Hands </em>
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- Large hands (in patients with PDGFRA mutations) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249752003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249752003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0426870&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0426870</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001176" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001176</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001176" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001176</a>]</span><br />
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<strong> SKIN, NAILS, & HAIR </strong>
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<div style="margin-left: 2em;">
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<span class="h5 mim-font">
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<em> Skin </em>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Hyperpigmentation (in patients with KIT mutations) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/4830009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">4830009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/49765009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">49765009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162834&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162834</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000953" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000953</a>]</span><br /> -
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Urticaria pigmentosa or cutaneous mastocytosis (in patients with KIT mutations) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675988&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675988</a>]</span><br />
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Tumors usually develop between 40 and 60 years of age<br /> -
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Both germline (familial) and somatic (sporadic) mutation in KIT (<a href="/entry/164920">164920</a>) and PDGFRA (<a href="/entry/173490">173490</a>) have been found<br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the V-KIT Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog gene (KIT, <a href="/entry/164920#0011">164920.0011</a>)<br /> -
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Caused by mutation in the platelet-derived growth factor receptor alpha gene (PDGFRA, <a href="/entry/173490#0001">173490.0001</a>)<br />
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</span>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<div>
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<br />
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that gastrointestinal stromal tumor (GIST) can be caused by heterozygous germline mutation in the KIT gene (<a href="/entry/164920">164920</a>) on chromosome 4q12. GISTs are also seen in patients with somatic mutation in the KIT gene.</p><p>Rare cases of GIST have been reported with germline mutation in the SDHB gene (<a href="/entry/185470">185470</a>) on chromosome 1p36 and the SDHC gene (<a href="/entry/602413">602413</a>) on chromosome 1q23.</p>
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<div>
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<br />
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<div class="mim-changed mim-change"><p>Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (Miettinen et al. (<a href="#15" class="mim-tip-reference" title="Miettinen, M., Monihan, J. M., Sarlomo-Rikala, M., Kovatich, A. J., Carr, N. J., Emory, T. S., Sobin, L. H. <strong>Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases.</strong> Am. J. Surg. Path. 23: 1109-1118, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10478672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10478672</a>] [<a href="https://doi.org/10.1097/00000478-199909000-00015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10478672">1999</a>, <a href="#16" class="mim-tip-reference" title="Miettinen, M., Sarlomo-Rikala, M., Lasota, J. <strong>Gastrointestinal stromal tumors: recent advances in understanding of their biology.</strong> Hum. Path. 30: 1213-1220, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10534170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10534170</a>] [<a href="https://doi.org/10.1016/s0046-8177(99)90040-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10534170">1999</a>)). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10534170+10478672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p>GISTs are also seen as a feature in several syndromes, e.g., neurofibromatosis-1 (NF1; <a href="/entry/162200">162200</a>) and GIST-plus syndrome (<a href="/entry/175510">175510</a>).</p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#17" class="mim-tip-reference" title="Nishida, T., Hirota, S., Taniguchi, M., Hashimoto, K., Isozaki, K., Nakamura, H., Kanakura, Y., Tanaka, T., Takabayashi, A., Matsuda, H., Kitamura, Y. <strong>Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. (Letter)</strong> Nature Genet. 19: 323-324, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697690</a>] [<a href="https://doi.org/10.1038/1209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9697690">Nishida et al. (1998)</a> reported a Japanese family in which 7 individuals spanning 4 generations had multiple GISTs. Inheritance was autosomal dominant. Most tumors were benign, but 1 patient had a malignant GIST. Two individuals reportedly had hyperpigmentation of the perineum. <a href="#17" class="mim-tip-reference" title="Nishida, T., Hirota, S., Taniguchi, M., Hashimoto, K., Isozaki, K., Nakamura, H., Kanakura, Y., Tanaka, T., Takabayashi, A., Matsuda, H., Kitamura, Y. <strong>Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. (Letter)</strong> Nature Genet. 19: 323-324, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697690</a>] [<a href="https://doi.org/10.1038/1209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9697690">Nishida et al. (1998)</a> noted that a woman reported by <a href="#7" class="mim-tip-reference" title="el-Omar, M., Davies, J., Gupta, S., Ross, H., Thompson, R. <strong>Leiomyosarcoma in leiomyomatosis of the small intestine.</strong> Postgrad. Med. J. 70: 661-664, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7971636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7971636</a>] [<a href="https://doi.org/10.1136/pgmj.70.827.661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7971636">el-Omar et al. (1994)</a> with multiple tumors that were probably GISTs also had hyperpigmentation of the perineal skin. In addition, <a href="#14" class="mim-tip-reference" title="Marshall, J. B., Diaz-Arias, A. A., Bochna, G. S., Vogele, K. A. <strong>Achalasia due to diffuse esophageal leiomyomatosis and inherited as an autosomal dominant disorder.</strong> Gastroenterology 98: 1358-1365, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2323526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2323526</a>] [<a href="https://doi.org/10.1016/0016-5085(90)90357-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2323526">Marshall et al. (1990)</a> reported a family in which several members suffered from benign GISTs associated with either cutaneous or systemic mastocytosis (see <a href="/entry/154800">154800</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2323526+7971636+9697690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Isozaki, K., Terris, B., Belghiti, J., Schiffmann, S., Hirota, S., Vanderwinden, J.-M. <strong>Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors.</strong> Am. J. Path. 157: 1581-1585, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11073817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11073817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11073817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S0002-9440(10)64795-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11073817">Isozaki et al. (2000)</a> reported a French mother and son, aged 67 and 40 years, with multiple macroscopic GISTs, measuring from 1 to 8 cm, in duodenum and jejunum. All tumors examined were of low malignancy grade and neither patient had metastases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11073817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Beghini, A., Tibiletti, M., Roversi, G., Chiaravalli, A., Serio, G., Capella, C., Larizza, L. <strong>Germline mutation in the juxtamembrane domain of the KIT gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa.</strong> Cancer 92: 657-662, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11505412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11505412</a>] [<a href="https://doi.org/10.1002/1097-0142(20010801)92:3<657::aid-cncr1367>3.0.co;2-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11505412">Beghini et al. (2001)</a> studied an Italian family in which 4 members over 3 generations, including a father and son, had multiple hyperpigmented spots. Both father and son had numerous dark-brown macules ranging in size from pinpoint dots to 5 mm and distributed on the skin of the face, trunk, extremities and mucous membranes. At 18 years of age, the father developed multiple GISTs with diffuse hyperplasia of the myenteric plexus; all tumors examined were benign or low malignancy-grade GISTs. The proband's 14-year-old son underwent evaluation of his skin lesions, and histology revealed groups of tightly packed round-to-ovoid mast cells around vessels of the upper and middle dermis; he was diagnosed with urticaria pigmentosa (see <a href="/entry/154800">154800</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11505412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Coffey, R. J., Washington, M. K., Corless, C. L., Heinrich, M. C. <strong>Menetrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach.</strong> J. Clin. Invest. 117: 70-80, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200708[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/JCI30491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200708">Coffey et al. (2007)</a> reviewed the clinical features, pathogenesis, and molecular treatments of Menetrier disease (<a href="/entry/137280">137280</a>) and GIST, both of which are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Until about 1990, most gastrointestinal sarcomas were considered to be leiomyosarcomas because they resembled smooth muscle histologically. However, clinical oncologists observed a distinctly lower rate of response to standard doxorubicin-based regimens among leiomyosarcomas that arose in the gut than among those that arose in the uterus, trunk, or arms and legs. As early as 1983 immunocytochemical studies of gastrointestinal sarcomas documented their frequent absence of muscle markers that were typical of leiomyosarcomas located elsewhere in the body. Tumors in the subgroup without muscle or Schwann-cell (i.e., S100 antigen) markers were eventually termed gastrointestinal stromal tumors. Almost all of these tumors expressed KIT (<a href="/entry/164920">164920</a>) and often CD34, both of which are also expressed on hematopoietic progenitor cells (Miettinen et al. (<a href="#15" class="mim-tip-reference" title="Miettinen, M., Monihan, J. M., Sarlomo-Rikala, M., Kovatich, A. J., Carr, N. J., Emory, T. S., Sobin, L. H. <strong>Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases.</strong> Am. J. Surg. Path. 23: 1109-1118, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10478672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10478672</a>] [<a href="https://doi.org/10.1097/00000478-199909000-00015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10478672">1999</a>, <a href="#16" class="mim-tip-reference" title="Miettinen, M., Sarlomo-Rikala, M., Lasota, J. <strong>Gastrointestinal stromal tumors: recent advances in understanding of their biology.</strong> Hum. Path. 30: 1213-1220, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10534170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10534170</a>] [<a href="https://doi.org/10.1016/s0046-8177(99)90040-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10534170">1999</a>)). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10534170+10478672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Chi, P., Chen, Y., Zhang, L., Guo, X., Wongvipat, J., Shamu, T., Fletcher, J. A., Dewell, S., Maki, R. G., Zheng, D., Antonescu, C. R., Allis, C. D., Sawyers, C. L. <strong>ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours.</strong> Nature 467: 849-853, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20927104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20927104</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20927104[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/nature09409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20927104">Chi et al. (2010)</a> demonstrated that ETV1 (<a href="/entry/600541">600541</a>) is highly expressed in the subtypes of interstitial cells of Cajal (ICCs) sensitive to oncogenic KIT-mediated transformation, and is required for their development. In addition, ETV1 is universally highly expressed in GISTs and is required for growth of imatinib-sensitive and -resistant GIST cell lines. Transcriptome profiling and global analyses of ETV1-binding sites suggested that ETV1 is a master regulator of an ICC-GIST-specific transcription network mainly through enhancer binding. The ETV1 transcriptional program is further regulated by activated KIT, which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. <a href="#3" class="mim-tip-reference" title="Chi, P., Chen, Y., Zhang, L., Guo, X., Wongvipat, J., Shamu, T., Fletcher, J. A., Dewell, S., Maki, R. G., Zheng, D., Antonescu, C. R., Allis, C. D., Sawyers, C. L. <strong>ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours.</strong> Nature 467: 849-853, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20927104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20927104</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20927104[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/nature09409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20927104">Chi et al. (2010)</a> proposed that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program. This model differs from other ETS-dependent tumors such as prostate cancer, melanoma, and Ewing sarcoma where genomic translocation or amplification drives aberrant ETS expression. <a href="#3" class="mim-tip-reference" title="Chi, P., Chen, Y., Zhang, L., Guo, X., Wongvipat, J., Shamu, T., Fletcher, J. A., Dewell, S., Maki, R. G., Zheng, D., Antonescu, C. R., Allis, C. D., Sawyers, C. L. <strong>ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours.</strong> Nature 467: 849-853, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20927104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20927104</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20927104[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/nature09409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20927104">Chi et al. (2010)</a> also stated that this model of GIST pathogenesis represents a novel mechanism of oncogenic transcription factor activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20927104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Janeway, K. A., Kim, S. Y., Lodish, M., Nose, V., Rustin, P., Gaal, J., Dahia, P. L. M., Liegl, B., Ball, E. R., Raygada, M., Lai, A. H., Kelly, L., and 10 others. <strong>Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations.</strong> Proc. Nat. Acad. Sci. 108: 314-318, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21173220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21173220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21173220[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1009199108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21173220">Janeway et al. (2011)</a> evaluated SDHB (<a href="/entry/185470">185470</a>) expression in 30 GISTs lacking KIT or PDGFRA (<a href="/entry/173490">173490</a>) mutations, 25 of which were also negative for associated SDH mutations confirmed by sequence analysis. Immunohistochemical studies showed lack of SDHB staining in 18 (100%) of 18 pediatric tumors, regardless of SDH mutation status, and in 8 (67%) of 12 adult tumors and weak expression in 4 (33%) of 12 adult tumors. By comparison, only 1 of 18 KIT-mutant GISTs and 0 of 5 NF1-associated GISTs lacked SDHB expression. These findings implicated a defect in respiration in the pathogenesis of some GIST tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21173220" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 subset of gastrointestinal stromal tumors (GISTs) lack canonical kinase mutations but instead have SDH deficiency and global DNA hypermethylation. <a href="#8" class="mim-tip-reference" title="Flavahan, W. A., Drier, Y., Johnstone, S. E., Hemming, M. L., Tarjan, D. R., Hegazi, E., Shareef, S. J., Javed, N. M., Raut, C. P., Eschle, B. K., Gokhale, P. C., Hornick, J. L., Sicinska, E. T., Demetri, G. D., Bernstein, B. E. <strong>Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs.</strong> Nature 575: 229-233, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31666694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31666694</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31666694[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1668-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31666694">Flavahan et al. (2019)</a> associated this hypermethylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, <a href="#8" class="mim-tip-reference" title="Flavahan, W. A., Drier, Y., Johnstone, S. E., Hemming, M. L., Tarjan, D. R., Hegazi, E., Shareef, S. J., Javed, N. M., Raut, C. P., Eschle, B. K., Gokhale, P. C., Hornick, J. L., Sicinska, E. T., Demetri, G. D., Bernstein, B. E. <strong>Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs.</strong> Nature 575: 229-233, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31666694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31666694</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31666694[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1668-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31666694">Flavahan et al. (2019)</a> mapped DNA methylation, CTCF (<a href="/entry/604167">604167</a>) insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant, and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, <a href="#8" class="mim-tip-reference" title="Flavahan, W. A., Drier, Y., Johnstone, S. E., Hemming, M. L., Tarjan, D. R., Hegazi, E., Shareef, S. J., Javed, N. M., Raut, C. P., Eschle, B. K., Gokhale, P. C., Hornick, J. L., Sicinska, E. T., Demetri, G. D., Bernstein, B. E. <strong>Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs.</strong> Nature 575: 229-233, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31666694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31666694</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31666694[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1668-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31666694">Flavahan et al. (2019)</a> identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. <a href="#8" class="mim-tip-reference" title="Flavahan, W. A., Drier, Y., Johnstone, S. E., Hemming, M. L., Tarjan, D. R., Hegazi, E., Shareef, S. J., Javed, N. M., Raut, C. P., Eschle, B. K., Gokhale, P. C., Hornick, J. L., Sicinska, E. T., Demetri, G. D., Bernstein, B. E. <strong>Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs.</strong> Nature 575: 229-233, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31666694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31666694</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31666694[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1668-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31666694">Flavahan et al. (2019)</a> focused on a disrupted insulator that normally partitions a core GIST superenhancer from the FGF4 (<a href="/entry/164980">164980</a>) oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary between enhancer and oncogene, and strongly upregulated FGF4 expression. <a href="#8" class="mim-tip-reference" title="Flavahan, W. A., Drier, Y., Johnstone, S. E., Hemming, M. L., Tarjan, D. R., Hegazi, E., Shareef, S. J., Javed, N. M., Raut, C. P., Eschle, B. K., Gokhale, P. C., Hornick, J. L., Sicinska, E. T., Demetri, G. D., Bernstein, B. E. <strong>Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs.</strong> Nature 575: 229-233, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31666694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31666694</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31666694[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1668-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31666694">Flavahan et al. (2019)</a> also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. The authors established a patient-derived xenograft from an SDH-deficient GIST that faithfully maintained the epigenetics of the parental tumor, including hypermethylation and insulator defects. This patient-derived xenograft model was highly sensitive to FGF receptor inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31666694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Imatinib, formerly referred to as STI571, is an inhibitor of specific protein tyrosine kinases. It is highly effective in the treatment of both chronic myeloid leukemia (CML; <a href="/entry/608232">608232</a>) and GISTs (<a href="#19" class="mim-tip-reference" title="Savage, D. G., Antman, K. H. <strong>Imatinib mesylate--a new oral targeted therapy.</strong> New Eng. J. Med. 346: 683-693, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11870247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11870247</a>] [<a href="https://doi.org/10.1056/NEJMra013339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11870247">Savage and Antman, 2002</a>). <a href="#13" class="mim-tip-reference" title="Joensuu, H., Roberts, P. J., Sarlomo-Rikala, M., Andersson, L. C., Tervahartiala, P., Tuveson, D., Silberman, S. L., Capdeville, R., Dimitrijevic, S., Druker, B., Demetri, G. D. <strong>Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor.</strong> New Eng. J. Med. 344: 1052-1056, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11287975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11287975</a>] [<a href="https://doi.org/10.1056/NEJM200104053441404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11287975">Joensuu et al. (2001)</a> described a Finnish patient with metastatic gastrointestinal stromal tumor who had a rapid and sustained complete response to treatment with imatinib daily for more than 12 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11287975+11870247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Balachandran, V. P., Cavnar, M. J., Zeng, S., Bamboat, Z. M., Ocuin, L. M., Obaid, H., Sorenson, E. C., Popow, R., Ariyan, C., Rossi, F., Besmer, P., Guo, T., Antonescu, C. R., Taguchi, T., Yuan, J., Wolchok, J. D., Allison, J. P., DeMatteo, R. P. <strong>Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.</strong> Nature Med. 17: 1094-1100, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21873989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21873989</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21873989[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/nm.2438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21873989">Balachandran et al. (2011)</a> found that KIT val558del mice (<a href="#20" class="mim-tip-reference" title="Sommer, G., Agosti, V., Ehlers, I., Rossi, F., Corbacioglu, S., Farkas, J., Moore, M., Manova, K., Antonescu, C. R., Besmer, P. <strong>Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase.</strong> Proc. Nat. Acad. Sci. 100: 6706-6711, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12754375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12754375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12754375[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1037763100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12754375">Sommer et al., 2003</a>) treated with imatinib had a rapid decrease in tumor weight and activity. This was associated with an increase in the number of activated CD8+ T cells and a decrease in the number of regulatory T cells within the tumor. Gene expression array indicated that these changes were mediated by reducing expression of the immunosuppressive enzyme IDO (<a href="/entry/147435">147435</a>) in tumor cells, whereas the expression of other immunomodulatory cytokines was not changed. In human GIST cells, imatinib inhibited KIT activation and IDO expression; IDO expression was also found to be regulated by mTOR (<a href="/entry/601231">601231</a>) and ETV4 (<a href="/entry/600711">600711</a>). In human GIST specimens, the CD8+ T cell profile correlated with sensitivity to imatinib and decreased IDO expression. Finally, in mice, concurrent immunotherapy using CTLA4 (<a href="/entry/123890">123890</a>) blockade augmented the efficacy of imatinib in GIST. The findings indicated that T cells are crucial to the antitumor effects of imatinib in GIST, and suggested that concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21873989+12754375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Germline Mutations in KIT</em></strong></p><p>
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In affected members of a Japanese family with multiple GISTs, <a href="#17" class="mim-tip-reference" title="Nishida, T., Hirota, S., Taniguchi, M., Hashimoto, K., Isozaki, K., Nakamura, H., Kanakura, Y., Tanaka, T., Takabayashi, A., Matsuda, H., Kitamura, Y. <strong>Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. (Letter)</strong> Nature Genet. 19: 323-324, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697690</a>] [<a href="https://doi.org/10.1038/1209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9697690">Nishida et al. (1998)</a> identified a germline deletion in the KIT gene (<a href="/entry/164920#0017">164920.0017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9697690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 French mother and son with multiple GISTs, <a href="#11" class="mim-tip-reference" title="Isozaki, K., Terris, B., Belghiti, J., Schiffmann, S., Hirota, S., Vanderwinden, J.-M. <strong>Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors.</strong> Am. J. Path. 157: 1581-1585, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11073817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11073817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11073817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S0002-9440(10)64795-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11073817">Isozaki et al. (2000)</a> identified a gain-of-function germline mutation in the KIT gene (K642E; <a href="/entry/164920#0024">164920.0024</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11073817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 an Italian man with multiple GISTs and hyperpigmented spots, <a href="#2" class="mim-tip-reference" title="Beghini, A., Tibiletti, M., Roversi, G., Chiaravalli, A., Serio, G., Capella, C., Larizza, L. <strong>Germline mutation in the juxtamembrane domain of the KIT gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa.</strong> Cancer 92: 657-662, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11505412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11505412</a>] [<a href="https://doi.org/10.1002/1097-0142(20010801)92:3<657::aid-cncr1367>3.0.co;2-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11505412">Beghini et al. (2001)</a> identified a germline mutation in the KIT gene (V559A; <a href="/entry/164920#0023">164920.0023</a>). His 14-year-old son, in whom the hyperpigmented lesions had been shown to represent cutaneous mastocytosis (MASTC; <a href="/entry/154800">154800</a>) also carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11505412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Germline Mutations in SDH Subunit Genes</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Janeway, K. A., Kim, S. Y., Lodish, M., Nose, V., Rustin, P., Gaal, J., Dahia, P. L. M., Liegl, B., Ball, E. R., Raygada, M., Lai, A. H., Kelly, L., and 10 others. <strong>Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations.</strong> Proc. Nat. Acad. Sci. 108: 314-318, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21173220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21173220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21173220[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1009199108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21173220">Janeway et al. (2011)</a> identified 3 germline mutations in the SDHB gene (see, e.g., <a href="/entry/185470#0004">185470.0004</a>) in 3 different patients with sporadic occurrence of GIST. The patients were 18, 22, and 21 years old, and none had a personal or family history of paragangliomas. Tumor tissue available from 2 of these patients showed lack of SDHB immunostaining. A fourth patient, who was 16 years old, carried a germline mutation in the SDHC gene (<a href="/entry/602413#0004">602413.0004</a>). Overall, mutations in SDH subunit genes accounted for 4 (12%) of 34 patients with isolated GIST lacking KIT or PDGFRA mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21173220" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Somatic Mutations</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Hirota, S., Isozaki, K., Moriyama, Y., Hashimoto, K., Nishida, T., Ishiguro, S., Kawano, K., Hanada, M., Kurata, A., Takeda, M., Tunio, G. M., Matsuzawa, Y., Kanakura, Y., Shinomura, Y., Kitamura, Y. <strong>Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.</strong> Science 279: 577-580, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9438854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9438854</a>] [<a href="https://doi.org/10.1126/science.279.5350.577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9438854">Hirota et al. (1998)</a> identified somatic gain-of-function mutations in the KIT gene (see, e.g., <a href="/entry/164920#0011">164920.0011</a>-<a href="/entry/164920#0015">164920.0015</a>) in 5 of 6 GISTs. Most GISTs were solitary and the mutations resulted in constitutive activation of the KIT gene. <a href="#16" class="mim-tip-reference" title="Miettinen, M., Sarlomo-Rikala, M., Lasota, J. <strong>Gastrointestinal stromal tumors: recent advances in understanding of their biology.</strong> Hum. Path. 30: 1213-1220, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10534170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10534170</a>] [<a href="https://doi.org/10.1016/s0046-8177(99)90040-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10534170">Miettinen et al. (1999)</a> stated that gastrointestinal stromal tumors with mutant KIT were more likely to be high-grade tumors, characterized by more frequent recurrences and a higher mortality rate compared to gastrointestinal stromal tumors with normal KIT. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10534170+9438854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Heinrich, M. C., Corless, C. L., Duensing, A., McGreevey, L., Chen, C.-J., Joseph, N., Singer, S., Griffith, D. J., Haley, A., Town, A., Demetri, G. D., Fletcher, C. D. M., Fletcher, J. A. <strong>PDGFRA activating mutations in gastrointestinal stromal tumors.</strong> Science 299: 708-710, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522257</a>] [<a href="https://doi.org/10.1126/science.1079666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522257">Heinrich et al. (2003)</a> found that approximately 35% (14 of 40) of GISTs lacking KIT mutations had somatic intragenic activation mutations in the PDGFRA gene (see, e.g., <a href="/entry/173490#0001">173490.0001</a>-<a href="/entry/173490#0007">173490.0007</a>). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. <a href="#9" class="mim-tip-reference" title="Heinrich, M. C., Corless, C. L., Duensing, A., McGreevey, L., Chen, C.-J., Joseph, N., Singer, S., Griffith, D. J., Haley, A., Town, A., Demetri, G. D., Fletcher, C. D. M., Fletcher, J. A. <strong>PDGFRA activating mutations in gastrointestinal stromal tumors.</strong> Science 299: 708-710, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522257</a>] [<a href="https://doi.org/10.1126/science.1079666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522257">Heinrich et al. (2003)</a> concluded that KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Modifier Genes</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Delahaye, N. F., Rusakiewicz, S., Martins, I., Menard, C., Roux, S., Lyonnet, L., Pascale, P., Sarabi, M., Chaput, N., Semeraro, M., Minard-Colin, V., Poirier-Colame, V., and 29 others. <strong>Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors.</strong> Nature Med. 17: 700-707, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21552268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21552268</a>] [<a href="https://doi.org/10.1038/nm.2366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21552268">Delahaye et al. (2011)</a> found an association between alternatively spliced exon 4 isoforms of the NCR3 gene (<a href="/entry/611550">611550</a>) and prognosis in GIST. In a study of 44 GIST tumors, tumor-infiltrating NK cells showed downregulation of NCR3 compared to circulating cells of healthy volunteers. The density of the NK cell infiltrate was inversely correlated with the presence of metastasis at diagnosis, suggesting an NK cell-mediated immunosurveillance mechanism in these tumors. RT-PCR studies of peripheral blood from 80 patients with GIST showed preferential expression of the immunosuppressive NCR3c isoform in 53%, compared to healthy volunteers, of whom only 30% expressed isoform NCR3c (p = 0.02). NK cells from GIST patients with the NCR3c isoform showed a defect in NCR3-driven NK effector functions. A retrospective analysis of 80 GIST patients treated with imatinib showed decreased overall survival in those with the NRC3c isoform compared to those with NRC3a and NRC3b isoforms (p = 0.001). <a href="#6" class="mim-tip-reference" title="Delahaye, N. F., Rusakiewicz, S., Martins, I., Menard, C., Roux, S., Lyonnet, L., Pascale, P., Sarabi, M., Chaput, N., Semeraro, M., Minard-Colin, V., Poirier-Colame, V., and 29 others. <strong>Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors.</strong> Nature Med. 17: 700-707, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21552268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21552268</a>] [<a href="https://doi.org/10.1038/nm.2366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21552268">Delahaye et al. (2011)</a> also found an association between a 3790T-C SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs986475;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs986475</a>) in the promoter region of the NCR3 gene, as well as other SNPs, and expression of the NCR3c isoform. The findings suggested that the genetically determined NCR3 status may predict clinical outcome in patients with GIST. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21552268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Reviews</em></strong></p><p>
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<a href="#18" class="mim-tip-reference" title="Sandberg, A. A., Bridge, J. A. <strong>Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: gastrointestinal stromal tumors.</strong> Cancer Genet. Cytogenet. 135: 1-22, 2002. Note: Erratum: Cancer Genet. Cytogenet. 137: 156 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12072198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12072198</a>] [<a href="https://doi.org/10.1016/s0165-4608(02)00546-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12072198">Sandberg and Bridge (2002)</a> reviewed the cytogenetics and molecular genetics of gastrointestinal stromal tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12072198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Patients with familial GISTs usually have multiple tumors; those with germline mutations in the KIT gene may also have hyperpigmentation, mast cell tumors, or dysphagia, whereas those with mutations in the PDGFRA gene often have large hands (<a href="#4" class="mim-tip-reference" title="Chompret, A., Kannengiesser, C., Barrois, M., Terrier, P., Dahan, P., Tursz, T., Lenoir, G. M., Bressac-De Paillerets, B. <strong>PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor.</strong> Gastroenterology 126: 318-321, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14699510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14699510</a>] [<a href="https://doi.org/10.1053/j.gastro.2003.10.079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14699510">Chompret et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14699510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>The form of familial GIST previously referred to as 'intestinal neurofibromatosis' and symbolized NF3B (or NF3) should not be confused with neurofibromatosis type III of Riccardi (<a href="/entry/162260">162260</a>), designated NF3A (or NF3).</p>
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<p>In a review, <a href="#5" class="mim-tip-reference" title="Coffey, R. J., Washington, M. K., Corless, C. L., Heinrich, M. C. <strong>Menetrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach.</strong> J. Clin. Invest. 117: 70-80, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200708[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/JCI30491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200708">Coffey et al. (2007)</a> stated that gain-of-function mutations in Kit lead to GIST in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Sommer, G., Agosti, V., Ehlers, I., Rossi, F., Corbacioglu, S., Farkas, J., Moore, M., Manova, K., Antonescu, C. R., Besmer, P. <strong>Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase.</strong> Proc. Nat. Acad. Sci. 100: 6706-6711, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12754375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12754375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12754375[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1037763100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12754375">Sommer et al. (2003)</a> generated a mouse model of GIST by knockin of a Kit exon 11-activating mutation, val558del, which corresponds to a val559del mutation (<a href="/entry/164920#0017">164920.0017</a>) found in human familial GISTs. Heterozygous male and female mice were fertile, but fertility was impaired with increasing age. Heterozygous mice developed symptoms of disease and eventually died from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells was evident within the myenteric plexus of the entire GI tract. Neoplastic lesions indistinguishable from human GISTs were observed in the cecum of the mutant mice with high penetrance. In addition, mast cell numbers in the dorsal skin were increased. <a href="#20" class="mim-tip-reference" title="Sommer, G., Agosti, V., Ehlers, I., Rossi, F., Corbacioglu, S., Farkas, J., Moore, M., Manova, K., Antonescu, C. R., Besmer, P. <strong>Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase.</strong> Proc. Nat. Acad. Sci. 100: 6706-6711, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12754375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12754375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12754375[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1037763100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12754375">Sommer et al. (2003)</a> concluded that mice heterozygous for a val558 deletion in the Kit gene reproduce human familial GISTs and may be used as a model for studying the role and mechanisms of Kit in neoplasia. Importantly, these results demonstrated that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12754375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1002/1097-0142(20010801)92:3<657::aid-cncr1367>3.0.co;2-d" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20927104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20927104</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20927104[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=20927104" 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/nature09409" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14699510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14699510</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14699510" 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/10.1053/j.gastro.2003.10.079" target="_blank">Full Text</a>]
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Coffey, R. J., Washington, M. K., Corless, C. L., Heinrich, M. C.
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<strong>Menetrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach.</strong>
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J. Clin. Invest. 117: 70-80, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200708[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=17200708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1079666" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.279.5350.577" target="_blank">Full Text</a>]
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Isozaki, K., Terris, B., Belghiti, J., Schiffmann, S., Hirota, S., Vanderwinden, J.-M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11073817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11073817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11073817[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=11073817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/S0002-9440(10)64795-5" target="_blank">Full Text</a>]
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<a id="Janeway2011" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21173220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21173220</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21173220[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=21173220" 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/10.1073/pnas.1009199108" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Joensuu2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Joensuu, H., Roberts, P. J., Sarlomo-Rikala, M., Andersson, L. C., Tervahartiala, P., Tuveson, D., Silberman, S. L., Capdeville, R., Dimitrijevic, S., Druker, B., Demetri, G. D.
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<strong>Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor.</strong>
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New Eng. J. Med. 344: 1052-1056, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11287975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11287975</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11287975" 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/NEJM200104053441404" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Marshall1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Marshall, J. B., Diaz-Arias, A. A., Bochna, G. S., Vogele, K. A.
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<strong>Achalasia due to diffuse esophageal leiomyomatosis and inherited as an autosomal dominant disorder.</strong>
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Gastroenterology 98: 1358-1365, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2323526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2323526</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2323526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0016-5085(90)90357-7" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
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<a id="Miettinen1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Miettinen, M., Monihan, J. M., Sarlomo-Rikala, M., Kovatich, A. J., Carr, N. J., Emory, T. S., Sobin, L. H.
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<strong>Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases.</strong>
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Am. J. Surg. Path. 23: 1109-1118, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10478672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10478672</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10478672" 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/10.1097/00000478-199909000-00015" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Miettinen1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Miettinen, M., Sarlomo-Rikala, M., Lasota, J.
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<strong>Gastrointestinal stromal tumors: recent advances in understanding of their biology.</strong>
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Hum. Path. 30: 1213-1220, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10534170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10534170</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10534170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0046-8177(99)90040-0" target="_blank">Full Text</a>]
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Nishida1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nishida, T., Hirota, S., Taniguchi, M., Hashimoto, K., Isozaki, K., Nakamura, H., Kanakura, Y., Tanaka, T., Takabayashi, A., Matsuda, H., Kitamura, Y.
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<strong>Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. (Letter)</strong>
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Nature Genet. 19: 323-324, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697690</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9697690" 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/10.1038/1209" target="_blank">Full Text</a>]
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<a id="18" class="mim-anchor"></a>
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<a id="Sandberg2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sandberg, A. A., Bridge, J. A.
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<strong>Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: gastrointestinal stromal tumors.</strong>
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Cancer Genet. Cytogenet. 135: 1-22, 2002. Note: Erratum: Cancer Genet. Cytogenet. 137: 156 only, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12072198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12072198</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12072198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0165-4608(02)00546-0" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Savage2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Savage, D. G., Antman, K. H.
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<strong>Imatinib mesylate--a new oral targeted therapy.</strong>
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New Eng. J. Med. 346: 683-693, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11870247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11870247</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11870247" 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/NEJMra013339" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
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<a id="Sommer2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sommer, G., Agosti, V., Ehlers, I., Rossi, F., Corbacioglu, S., Farkas, J., Moore, M., Manova, K., Antonescu, C. R., Besmer, P.
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<strong>Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase.</strong>
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Proc. Nat. Acad. Sci. 100: 6706-6711, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12754375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12754375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12754375[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=12754375" 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/10.1073/pnas.1037763100" target="_blank">Full Text</a>]
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</ol>
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<div>
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<br />
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 12/09/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 07/12/2019<br>Marla J. F. O'Neill - updated : 07/12/2018<br>Cassandra L. Kniffin - updated : 12/15/2011<br>Cassandra L. Kniffin - updated : 9/6/2011<br>Cassandra L. Kniffin - updated : 6/2/2011<br>Ada Hamosh - updated : 11/11/2010<br>Cassandra L. Kniffin - updated : 4/2/2008<br>Marla J. F. O'Neill - updated : 4/11/2006<br>Ada Hamosh - updated : 2/13/2003<br>Victor A. McKusick - updated : 10/17/2002
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 3/15/2002
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/27/2025
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 12/09/2019<br>carol : 07/13/2019<br>carol : 07/12/2019<br>carol : 07/12/2018<br>carol : 10/10/2016<br>terry : 12/20/2012<br>carol : 3/21/2012<br>terry : 3/21/2012<br>ckniffin : 12/15/2011<br>carol : 9/7/2011<br>ckniffin : 9/6/2011<br>wwang : 6/9/2011<br>ckniffin : 6/2/2011<br>alopez : 11/12/2010<br>alopez : 11/12/2010<br>terry : 11/11/2010<br>carol : 4/4/2008<br>carol : 4/4/2008<br>ckniffin : 4/2/2008<br>mgross : 4/12/2007<br>carol : 4/13/2006<br>terry : 4/11/2006<br>alopez : 11/17/2003<br>tkritzer : 6/25/2003<br>alopez : 2/19/2003<br>terry : 2/13/2003<br>carol : 10/17/2002<br>terry : 6/26/2002<br>alopez : 3/15/2002<br>alopez : 3/15/2002
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</span>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 606764
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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GASTROINTESTINAL STROMAL TUMOR; GIST
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1187383001, 128755003, 420120006;
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<strong>ICD10CM:</strong> C49.A;
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<strong>ORPHA:</strong> 44890;
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<strong>DO:</strong> 9253;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
|
Inheritance
|
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</th>
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
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<th>
|
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Gene/Locus
|
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</th>
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<th>
|
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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1p36.13
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Gastrointestinal stromal tumor
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
606764
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Autosomal dominant; Isolated cases
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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<td>
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<span class="mim-font">
|
|
SDHB
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
185470
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
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1q23.3
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Gastrointestinal stromal tumor
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
606764
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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Autosomal dominant; Isolated cases
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
|
3
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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SDHC
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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602413
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<span class="mim-font">
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4q12
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<span class="mim-font">
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Gastrointestinal stromal tumor, familial
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<span class="mim-font">
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606764
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<span class="mim-font">
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Autosomal dominant; Isolated cases
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<span class="mim-font">
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3
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<span class="mim-font">
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KIT
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<span class="mim-font">
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164920
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that gastrointestinal stromal tumor (GIST) can be caused by heterozygous germline mutation in the KIT gene (164920) on chromosome 4q12. GISTs are also seen in patients with somatic mutation in the KIT gene.</p><p>Rare cases of GIST have been reported with germline mutation in the SDHB gene (185470) on chromosome 1p36 and the SDHC gene (602413) on chromosome 1q23.</p>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (Miettinen et al. (1999, 1999)). </p><p>GISTs are also seen as a feature in several syndromes, e.g., neurofibromatosis-1 (NF1; 162200) and GIST-plus syndrome (175510).</p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Nishida et al. (1998) reported a Japanese family in which 7 individuals spanning 4 generations had multiple GISTs. Inheritance was autosomal dominant. Most tumors were benign, but 1 patient had a malignant GIST. Two individuals reportedly had hyperpigmentation of the perineum. Nishida et al. (1998) noted that a woman reported by el-Omar et al. (1994) with multiple tumors that were probably GISTs also had hyperpigmentation of the perineal skin. In addition, Marshall et al. (1990) reported a family in which several members suffered from benign GISTs associated with either cutaneous or systemic mastocytosis (see 154800). </p><p>Isozaki et al. (2000) reported a French mother and son, aged 67 and 40 years, with multiple macroscopic GISTs, measuring from 1 to 8 cm, in duodenum and jejunum. All tumors examined were of low malignancy grade and neither patient had metastases. </p><p>Beghini et al. (2001) studied an Italian family in which 4 members over 3 generations, including a father and son, had multiple hyperpigmented spots. Both father and son had numerous dark-brown macules ranging in size from pinpoint dots to 5 mm and distributed on the skin of the face, trunk, extremities and mucous membranes. At 18 years of age, the father developed multiple GISTs with diffuse hyperplasia of the myenteric plexus; all tumors examined were benign or low malignancy-grade GISTs. The proband's 14-year-old son underwent evaluation of his skin lesions, and histology revealed groups of tightly packed round-to-ovoid mast cells around vessels of the upper and middle dermis; he was diagnosed with urticaria pigmentosa (see 154800). </p><p>Coffey et al. (2007) reviewed the clinical features, pathogenesis, and molecular treatments of Menetrier disease (137280) and GIST, both of which are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases. </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>Pathogenesis</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>Until about 1990, most gastrointestinal sarcomas were considered to be leiomyosarcomas because they resembled smooth muscle histologically. However, clinical oncologists observed a distinctly lower rate of response to standard doxorubicin-based regimens among leiomyosarcomas that arose in the gut than among those that arose in the uterus, trunk, or arms and legs. As early as 1983 immunocytochemical studies of gastrointestinal sarcomas documented their frequent absence of muscle markers that were typical of leiomyosarcomas located elsewhere in the body. Tumors in the subgroup without muscle or Schwann-cell (i.e., S100 antigen) markers were eventually termed gastrointestinal stromal tumors. Almost all of these tumors expressed KIT (164920) and often CD34, both of which are also expressed on hematopoietic progenitor cells (Miettinen et al. (1999, 1999)). </p><p>Chi et al. (2010) demonstrated that ETV1 (600541) is highly expressed in the subtypes of interstitial cells of Cajal (ICCs) sensitive to oncogenic KIT-mediated transformation, and is required for their development. In addition, ETV1 is universally highly expressed in GISTs and is required for growth of imatinib-sensitive and -resistant GIST cell lines. Transcriptome profiling and global analyses of ETV1-binding sites suggested that ETV1 is a master regulator of an ICC-GIST-specific transcription network mainly through enhancer binding. The ETV1 transcriptional program is further regulated by activated KIT, which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. Chi et al. (2010) proposed that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program. This model differs from other ETS-dependent tumors such as prostate cancer, melanoma, and Ewing sarcoma where genomic translocation or amplification drives aberrant ETS expression. Chi et al. (2010) also stated that this model of GIST pathogenesis represents a novel mechanism of oncogenic transcription factor activation. </p><p>Janeway et al. (2011) evaluated SDHB (185470) expression in 30 GISTs lacking KIT or PDGFRA (173490) mutations, 25 of which were also negative for associated SDH mutations confirmed by sequence analysis. Immunohistochemical studies showed lack of SDHB staining in 18 (100%) of 18 pediatric tumors, regardless of SDH mutation status, and in 8 (67%) of 12 adult tumors and weak expression in 4 (33%) of 12 adult tumors. By comparison, only 1 of 18 KIT-mutant GISTs and 0 of 5 NF1-associated GISTs lacked SDHB expression. These findings implicated a defect in respiration in the pathogenesis of some GIST tumors. </p><p>A subset of gastrointestinal stromal tumors (GISTs) lack canonical kinase mutations but instead have SDH deficiency and global DNA hypermethylation. Flavahan et al. (2019) associated this hypermethylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, Flavahan et al. (2019) mapped DNA methylation, CTCF (604167) insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant, and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, Flavahan et al. (2019) identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. Flavahan et al. (2019) focused on a disrupted insulator that normally partitions a core GIST superenhancer from the FGF4 (164980) oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary between enhancer and oncogene, and strongly upregulated FGF4 expression. Flavahan et al. (2019) also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. The authors established a patient-derived xenograft from an SDH-deficient GIST that faithfully maintained the epigenetics of the parental tumor, including hypermethylation and insulator defects. This patient-derived xenograft model was highly sensitive to FGF receptor inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. </p>
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</span>
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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>Clinical Management</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>Imatinib, formerly referred to as STI571, is an inhibitor of specific protein tyrosine kinases. It is highly effective in the treatment of both chronic myeloid leukemia (CML; 608232) and GISTs (Savage and Antman, 2002). Joensuu et al. (2001) described a Finnish patient with metastatic gastrointestinal stromal tumor who had a rapid and sustained complete response to treatment with imatinib daily for more than 12 months. </p><p>Balachandran et al. (2011) found that KIT val558del mice (Sommer et al., 2003) treated with imatinib had a rapid decrease in tumor weight and activity. This was associated with an increase in the number of activated CD8+ T cells and a decrease in the number of regulatory T cells within the tumor. Gene expression array indicated that these changes were mediated by reducing expression of the immunosuppressive enzyme IDO (147435) in tumor cells, whereas the expression of other immunomodulatory cytokines was not changed. In human GIST cells, imatinib inhibited KIT activation and IDO expression; IDO expression was also found to be regulated by mTOR (601231) and ETV4 (600711). In human GIST specimens, the CD8+ T cell profile correlated with sensitivity to imatinib and decreased IDO expression. Finally, in mice, concurrent immunotherapy using CTLA4 (123890) blockade augmented the efficacy of imatinib in GIST. The findings indicated that T cells are crucial to the antitumor effects of imatinib in GIST, and suggested that concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents. </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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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Germline Mutations in KIT</em></strong></p><p>
|
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In affected members of a Japanese family with multiple GISTs, Nishida et al. (1998) identified a germline deletion in the KIT gene (164920.0017). </p><p>In a French mother and son with multiple GISTs, Isozaki et al. (2000) identified a gain-of-function germline mutation in the KIT gene (K642E; 164920.0024). </p><p>In an Italian man with multiple GISTs and hyperpigmented spots, Beghini et al. (2001) identified a germline mutation in the KIT gene (V559A; 164920.0023). His 14-year-old son, in whom the hyperpigmented lesions had been shown to represent cutaneous mastocytosis (MASTC; 154800) also carried the mutation. </p><p><strong><em>Germline Mutations in SDH Subunit Genes</em></strong></p><p>
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Janeway et al. (2011) identified 3 germline mutations in the SDHB gene (see, e.g., 185470.0004) in 3 different patients with sporadic occurrence of GIST. The patients were 18, 22, and 21 years old, and none had a personal or family history of paragangliomas. Tumor tissue available from 2 of these patients showed lack of SDHB immunostaining. A fourth patient, who was 16 years old, carried a germline mutation in the SDHC gene (602413.0004). Overall, mutations in SDH subunit genes accounted for 4 (12%) of 34 patients with isolated GIST lacking KIT or PDGFRA mutations. </p><p><strong><em>Somatic Mutations</em></strong></p><p>
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Hirota et al. (1998) identified somatic gain-of-function mutations in the KIT gene (see, e.g., 164920.0011-164920.0015) in 5 of 6 GISTs. Most GISTs were solitary and the mutations resulted in constitutive activation of the KIT gene. Miettinen et al. (1999) stated that gastrointestinal stromal tumors with mutant KIT were more likely to be high-grade tumors, characterized by more frequent recurrences and a higher mortality rate compared to gastrointestinal stromal tumors with normal KIT. </p><p>Heinrich et al. (2003) found that approximately 35% (14 of 40) of GISTs lacking KIT mutations had somatic intragenic activation mutations in the PDGFRA gene (see, e.g., 173490.0001-173490.0007). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Heinrich et al. (2003) concluded that KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs. </p><p><strong><em>Modifier Genes</em></strong></p><p>
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Delahaye et al. (2011) found an association between alternatively spliced exon 4 isoforms of the NCR3 gene (611550) and prognosis in GIST. In a study of 44 GIST tumors, tumor-infiltrating NK cells showed downregulation of NCR3 compared to circulating cells of healthy volunteers. The density of the NK cell infiltrate was inversely correlated with the presence of metastasis at diagnosis, suggesting an NK cell-mediated immunosurveillance mechanism in these tumors. RT-PCR studies of peripheral blood from 80 patients with GIST showed preferential expression of the immunosuppressive NCR3c isoform in 53%, compared to healthy volunteers, of whom only 30% expressed isoform NCR3c (p = 0.02). NK cells from GIST patients with the NCR3c isoform showed a defect in NCR3-driven NK effector functions. A retrospective analysis of 80 GIST patients treated with imatinib showed decreased overall survival in those with the NRC3c isoform compared to those with NRC3a and NRC3b isoforms (p = 0.001). Delahaye et al. (2011) also found an association between a 3790T-C SNP (rs986475) in the promoter region of the NCR3 gene, as well as other SNPs, and expression of the NCR3c isoform. The findings suggested that the genetically determined NCR3 status may predict clinical outcome in patients with GIST. </p><p><strong><em>Reviews</em></strong></p><p>
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Sandberg and Bridge (2002) reviewed the cytogenetics and molecular genetics of gastrointestinal stromal tumors. </p>
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</span>
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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>Genotype/Phenotype Correlations</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>Patients with familial GISTs usually have multiple tumors; those with germline mutations in the KIT gene may also have hyperpigmentation, mast cell tumors, or dysphagia, whereas those with mutations in the PDGFRA gene often have large hands (Chompret et al., 2004). </p>
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</span>
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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>Nomenclature</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>The form of familial GIST previously referred to as 'intestinal neurofibromatosis' and symbolized NF3B (or NF3) should not be confused with neurofibromatosis type III of Riccardi (162260), designated NF3A (or NF3).</p>
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</span>
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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>In a review, Coffey et al. (2007) stated that gain-of-function mutations in Kit lead to GIST in mice. </p><p>Sommer et al. (2003) generated a mouse model of GIST by knockin of a Kit exon 11-activating mutation, val558del, which corresponds to a val559del mutation (164920.0017) found in human familial GISTs. Heterozygous male and female mice were fertile, but fertility was impaired with increasing age. Heterozygous mice developed symptoms of disease and eventually died from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells was evident within the myenteric plexus of the entire GI tract. Neoplastic lesions indistinguishable from human GISTs were observed in the cecum of the mutant mice with high penetrance. In addition, mast cell numbers in the dorsal skin were increased. Sommer et al. (2003) concluded that mice heterozygous for a val558 deletion in the Kit gene reproduce human familial GISTs and may be used as a model for studying the role and mechanisms of Kit in neoplasia. Importantly, these results demonstrated that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<p class="mim-text-font">
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Balachandran, V. P., Cavnar, M. J., Zeng, S., Bamboat, Z. M., Ocuin, L. M., Obaid, H., Sorenson, E. C., Popow, R., Ariyan, C., Rossi, F., Besmer, P., Guo, T., Antonescu, C. R., Taguchi, T., Yuan, J., Wolchok, J. D., Allison, J. P., DeMatteo, R. P.
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<strong>Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.</strong>
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Nature Med. 17: 1094-1100, 2011.
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[PubMed: 21873989]
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[Full Text: https://doi.org/10.1038/nm.2438]
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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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Beghini, A., Tibiletti, M., Roversi, G., Chiaravalli, A., Serio, G., Capella, C., Larizza, L.
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<strong>Germline mutation in the juxtamembrane domain of the KIT gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa.</strong>
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Cancer 92: 657-662, 2001.
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[PubMed: 11505412]
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[Full Text: https://doi.org/10.1002/1097-0142(20010801)92:3<657::aid-cncr1367>3.0.co;2-d]
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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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Chi, P., Chen, Y., Zhang, L., Guo, X., Wongvipat, J., Shamu, T., Fletcher, J. A., Dewell, S., Maki, R. G., Zheng, D., Antonescu, C. R., Allis, C. D., Sawyers, C. L.
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<strong>ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours.</strong>
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Nature 467: 849-853, 2010.
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[PubMed: 20927104]
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[Full Text: https://doi.org/10.1038/nature09409]
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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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Chompret, A., Kannengiesser, C., Barrois, M., Terrier, P., Dahan, P., Tursz, T., Lenoir, G. M., Bressac-De Paillerets, B.
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<strong>PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor.</strong>
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Gastroenterology 126: 318-321, 2004.
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[PubMed: 14699510]
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[Full Text: https://doi.org/10.1053/j.gastro.2003.10.079]
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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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Coffey, R. J., Washington, M. K., Corless, C. L., Heinrich, M. C.
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<strong>Menetrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach.</strong>
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J. Clin. Invest. 117: 70-80, 2007.
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[PubMed: 17200708]
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[Full Text: https://doi.org/10.1172/JCI30491]
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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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Delahaye, N. F., Rusakiewicz, S., Martins, I., Menard, C., Roux, S., Lyonnet, L., Pascale, P., Sarabi, M., Chaput, N., Semeraro, M., Minard-Colin, V., Poirier-Colame, V., and 29 others.
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<strong>Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors.</strong>
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Nature Med. 17: 700-707, 2011.
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[PubMed: 21552268]
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[Full Text: https://doi.org/10.1038/nm.2366]
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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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el-Omar, M., Davies, J., Gupta, S., Ross, H., Thompson, R.
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<strong>Leiomyosarcoma in leiomyomatosis of the small intestine.</strong>
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Postgrad. Med. J. 70: 661-664, 1994.
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[PubMed: 7971636]
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[Full Text: https://doi.org/10.1136/pgmj.70.827.661]
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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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Flavahan, W. A., Drier, Y., Johnstone, S. E., Hemming, M. L., Tarjan, D. R., Hegazi, E., Shareef, S. J., Javed, N. M., Raut, C. P., Eschle, B. K., Gokhale, P. C., Hornick, J. L., Sicinska, E. T., Demetri, G. D., Bernstein, B. E.
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<strong>Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs.</strong>
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Nature 575: 229-233, 2019.
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