3589 lines
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Entry
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- #109800 - BLADDER CANCER
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- OMIM
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<p>
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<span class="h4">#109800</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/109800"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#clinicalFeatures">Clinical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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</span>
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</span>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div><a href="https://clinicaltrials.gov/search?cond=(BLADDER CANCER) OR (HRAS OR KRAS OR FGFR3 OR RB1)" 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.diseaseinfosearch.org/x/7822" 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/bladder-cancer" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=109800[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:11054" 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/109800" 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/results?search_type=advanced&omia_id=001512,001990" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:11054" 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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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 399326009<br />
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<strong>ICD10CM:</strong> C67, C67.9<br />
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<strong>ICD9CM:</strong> 188, 188.9<br />
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<strong>DO:</strong> 11054<br />
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">ICD+</a>
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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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109800
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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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|
BLADDER CANCER
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="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/4/34?start=-3&limit=10&highlight=34">
|
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4p16.3
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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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Bladder cancer, somatic
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/109800"> 109800 </a>
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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FGFR3
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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/134934"> 134934 </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/11/29?start=-3&limit=10&highlight=29">
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11p15.5
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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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Bladder cancer, somatic
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/109800"> 109800 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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HRAS
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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/190020"> 190020 </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/12/240?start=-3&limit=10&highlight=240">
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12p12.1
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Bladder cancer, somatic
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<span class="mim-font">
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<a href="/entry/109800"> 109800 </a>
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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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KRAS
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<span class="mim-font">
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<a href="/entry/190070"> 190070 </a>
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<span class="mim-font">
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<a href="/geneMap/13/162?start=-3&limit=10&highlight=162">
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13q14.2
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<span class="mim-font">
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Bladder cancer, somatic
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<span class="mim-font">
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<a href="/entry/109800"> 109800 </a>
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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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RB1
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<span class="mim-font">
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<a href="/entry/614041"> 614041 </a>
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<a href="/clinicalSynopsis/109800" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<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')">
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<span class="sr-only">Toggle Dropdown</span>
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/109800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/109800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Somatic mutation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/124975008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">124975008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866227</a>, <a href="https://bioportal.bioontology.org/search?q=C0544886&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0544886</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</a>]</span><br />
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> NEOPLASIA </strong>
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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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- Bladder cancer <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399326009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399326009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/126885006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">126885006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255108000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255108000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C67.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C67.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/C67" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C67</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/188.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">188.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/188" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">188</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0699885&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0699885</a>, <a href="https://bioportal.bioontology.org/search?q=C0005695&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005695</a>, <a href="https://bioportal.bioontology.org/search?q=C0005684&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005684</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009725" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009725</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002862" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002862</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009725" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009725</a>]</span><br /> -
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Transitional cell bladder carcinoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255109008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255109008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0279680&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0279680</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006740" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006740</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006740" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006740</a>]</span><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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<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 somatic mutation in the fibroblast growth factor receptor 3 gene (FGFR3, <a href="/entry/134934#0013">134934.0013</a>)<br /> -
|
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Caused by somatic mutation in the KRAS protooncogene, GTPase, gene (KRAS, <a href="/entry/190070#0002">190070.0002</a>)<br /> -
|
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Caused by somatic mutation in the HRAS protooncogene, GTPase, gene (HRAS, <a href="/entry/190020#0001">190020.0001</a>)<br /> -
|
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Caused by somatic mutation in the RB transcriptional corepressor 1 gene (RB1, <a href="/entry/614041#0009">614041.0009</a>)<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 class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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<div>
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<br />
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<div>
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<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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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because bladder cancer is a complex disorder with both genetic and environmental influences. Somatic mutations in several genes, e.g., HRAS (<a href="/entry/190020">190020</a>), KRAS2 (<a href="/entry/190070">190070</a>), RB1 (<a href="/entry/614041">614041</a>), and FGFR3 (<a href="/entry/134934">134934</a>), have been implicated in bladder carcinogenesis. See <a href="#2" class="mim-tip-reference" title="Bishop, J. M. <strong>Oncogenes.</strong> Sci. Am. 246(3): 80-92, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6281879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6281879</a>] [<a href="https://doi.org/10.1038/scientificamerican0382-80" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6281879">Bishop (1982)</a> for a discussion of oncogenes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6281879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<br />
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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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</h4>
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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>Patients with cancer of the urinary bladder often present with multiple tumors appearing at different times and at different sites in the bladder. This observation had been attributed to a 'field defect' in the bladder that allowed the independent transformation of epithelial cells at a number of sites. <a href="#31" class="mim-tip-reference" title="Sidransky, D., Frost, P., Von Eschenbach, A., Oyasu, R., Preisinger, A. C., Vogelstein, B. <strong>Clonal origin of bladder cancer.</strong> New Eng. J. Med. 326: 737-740, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1445507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1445507</a>] [<a href="https://doi.org/10.1056/NEJM199203123261104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1445507">Sidransky et al. (1992)</a> tested this hypothesis with molecular genetic techniques and concluded that in fact multiple bladder tumors are of clonal origin. A number of bladder tumors can arise from the uncontrolled spread of a single transformed cell. These tumors can then grow independently with variable subsequent genetic alterations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1445507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Dyrskjot, L., Thykjaer, T., Kruhoffer, M., Jensen, J. L., Marcussen, N., Hamilton-Dutoit, S., Wolf, H., Orntoft, T. F. <strong>Identifying distinct classes of bladder carcinoma using microarrays.</strong> Nature Genet. 33: 90-96, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12469123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12469123</a>] [<a href="https://doi.org/10.1038/ng1061" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12469123">Dyrskjot et al. (2003)</a> reported the identification of clinically relevant subclasses of bladder carcinoma using expression microarray analysis of 40 well-characterized bladder tumors. Gene expression profiles characterizing each stage and subtype identified their biologic properties, producing potential targets for therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12469123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Inheritance</strong>
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<p><a href="#9" class="mim-tip-reference" title="Fraumeni, J. F., Jr., Thomas, L. B. <strong>Malignant bladder tumors in a family.</strong> JAMA 201: 507-509, 1967."None>Fraumeni and Thomas (1967)</a> observed affected father and 3 sons. <a href="#25" class="mim-tip-reference" title="McKusick, V. A. <strong>Personal Communication.</strong> Baltimore, Md. 1972."None>McKusick (1972)</a> encountered 2 instances of affected father and son at the Johns Hopkins Hospital. <a href="#24" class="mim-tip-reference" title="McCullough, D. L., Lamm, D. L., McLaughlin, A. P., III, Gittes, R. F. <strong>Familial transitional cell carcinoma of the bladder.</strong> J. Urol. 113: 629-635, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1127804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1127804</a>] [<a href="https://doi.org/10.1016/s0022-5347(17)59540-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1127804">McCullough et al. (1975)</a> found transitional cell carcinoma (TCC) in 6 persons in 3 sibships of 2 generations of a kindred. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1127804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 review of case reports and epidemiologic studies in the literature, <a href="#19" class="mim-tip-reference" title="Kiemeney, L. A. L. M., Schoenberg, M. <strong>Familial transitional cell carcinoma.</strong> J. Urol. 156: 867-872, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8709350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8709350</a>]" pmid="8709350">Kiemeney and Schoenberg (1996)</a> concluded that first-degree relatives have an increased risk for TCC by a factor of 2. Familial clustering of smoking did not appear to be the cause of this increased risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8709350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Iceland, <a href="#16" class="mim-tip-reference" title="Kiemeney, L. A., Moret, N. C., Witjes, J. A., Schoenberg, M. P., Tulinius, H. <strong>Familial transitional cell carcinoma among the population of Iceland.</strong> J. Urol. 157: 1649-1651, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9112497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9112497</a>]" pmid="9112497">Kiemeney et al. (1997)</a> studied the first- to third-degree relatives of 190 patients with bladder, ureter, or renal pelvis TCC diagnosed between 1983 and 1992. In 41 of the 190 pedigrees, at least 1 relative had TCC of the urinary tract. Of the probands, 38 had only 1 and 3 had 2 affected relatives. The prevalence of family history of TCC was 3% in first-degree and 10% in first- or second-degree relatives. The risk of TCC among all relatives was slightly elevated, the observed-to-expected ratio being greater among second- and third-degree relatives than among first-degree relatives. <a href="#16" class="mim-tip-reference" title="Kiemeney, L. A., Moret, N. C., Witjes, J. A., Schoenberg, M. P., Tulinius, H. <strong>Familial transitional cell carcinoma among the population of Iceland.</strong> J. Urol. 157: 1649-1651, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9112497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9112497</a>]" pmid="9112497">Kiemeney et al. (1997)</a> concluded that the greater risk among distant relatives argues against the existence of a hereditary subtype of bladder TCC, at least in the founder population of Iceland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9112497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Goldfarb, M., Shimizu, K., Perucho, M., Wigler, M. <strong>Isolation and preliminary characterization of a human transforming gene from T24 bladder carcinoma cells.</strong> Nature 296: 404-409, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7063039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7063039</a>] [<a href="https://doi.org/10.1038/296404a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7063039">Goldfarb et al. (1982)</a> studied the DNA from T24, a cell line derived from a human bladder carcinoma, which can induce the morphologic transformation of nonmalignant cells. The gene responsible for this transformation was cloned by techniques of gene rescue: it was shown to be human in origin and less than 5 kb long. By Southern blot analysis of human-rodent hybrid cell DNA, <a href="#6" class="mim-tip-reference" title="de Martinville, B., Giacalone, J., Shih, C., Weinberg, R. A., Francke, U. <strong>Oncogene from human EJ bladder carcinoma is located on the short arm of chromosome 11.</strong> Science 219: 498-501, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6297001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6297001</a>] [<a href="https://doi.org/10.1126/science.6297001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6297001">de Martinville et al. (1983)</a> found that the cellular homolog of the transforming DNA sequence isolated from the bladder carcinoma line EJ is located on the short arm of chromosome 11, which contains sequences homologous to the HRAS (<a href="/entry/190020">190020</a>) oncogene. No evidence of gene amplification was found. These workers also found karyologically 'a complex rearrangement of the short arm in two of the four copies of chromosome 11 present in this heteroploid cell line' (EJ). <a href="#29" class="mim-tip-reference" title="Shih, C., Padhy, L. C., Murray, M., Weinberg, R. A. <strong>Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts.</strong> Nature 290: 261-264, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7207618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7207618</a>] [<a href="https://doi.org/10.1038/290261a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7207618">Shih et al. (1981)</a> found that DNA from mouse and rabbit bladder cancers as well as from the human bladder cancer cell line EJ induced foci of transformed cells when applied to monolayer cultures of NIH3T3 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6297001+7207618+7063039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Deletions involving chromosome 9 represent the most frequent genetic change identified in bladder tumors. Several independent studies had reported overall deletion frequencies of 50 to 70% in large series of tumors (see review by <a href="#28" class="mim-tip-reference" title="Sandberg, A. A. <strong>Cytogenetics and molecular genetics of bladder cancer: a personal view.</strong> Am. J. Med. Genet. 115: 173-182, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12407698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12407698</a>] [<a href="https://doi.org/10.1002/ajmg.10693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12407698">Sandberg, 2002</a>). It was of particular interest that these deletions were present at similar frequency in bladder tumors of all grades and stages (<a href="#33" class="mim-tip-reference" title="Tsai, Y. C., Nichols, P. W., Hiti, A. L., Williams, Z., Skinner, D. G., Jones, P. A. <strong>Allelic losses of chromosomes 9, 11, and 17 in human bladder cancer.</strong> Cancer Res. 50: 44-47, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2293558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2293558</a>]" pmid="2293558">Tsai et al., 1990</a>). This finding of chromosome 9 deletions as the sole genetic change in many low-grade, early-stage tumors suggests that it may represent an early or initiating genetic event. <a href="#15" class="mim-tip-reference" title="Keen, A. J., Knowles, M. A. <strong>Definition of two regions of deletion on chromosome 9 in carcinoma of the bladder.</strong> Oncogene 9: 2083-2088, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8208555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8208555</a>]" pmid="8208555">Keen and Knowles (1994)</a> used a panel of 22 highly informative microsatellite markers, evenly distributed along chromosome 9, to analyze LOH in 95 cases of primary TCC of the bladder. In 49 tumors (53%), LOH was demonstrated at one or more loci. Of these 49, 30 had LOH at all informative loci, indicating probable monosomy 9. Subchromosomal deletions were found in 19 tumors (22%), 5 of 9p only, 9 of 9q only, and 5 of both 9p and 9q with a clear region of retention of heterozygosity between. The patterns of LOH in these tumors indicated a common region of deletion on 9p between D9S126 (9p21) and the interferon-alpha cluster (IFNA; <a href="/entry/147660">147660</a>) located also at 9p21. A single tumor showed a second site of deletion on 9p telomeric to IFNA, indicating the possible existence of 2 target genes on 9p. All deletions of 9q were large, with a common region of deletion between D9S15 (9q13-q21.1) and D9S60 (9q33-q34.1). The results provided evidence for the simultaneous involvement of distinct suppressor loci on 9p and 9q in bladder carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12407698+2293558+8208555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of loss of heterozygosity (LOH), <a href="#30" class="mim-tip-reference" title="Shipman, R., Schraml, P., Colombi, M., Raefle, G., Ludwig, C. U. <strong>Loss of heterozygosity on chromosome 11p13 in primary bladder carcinoma.</strong> Hum. Genet. 91: 455-458, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8100210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8100210</a>] [<a href="https://doi.org/10.1007/BF00217771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8100210">Shipman et al. (1993)</a> found no evidence of deletion at 17p13, the region known to contain the p53 tumor suppressor gene (TP53; <a href="/entry/191170">191170</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8100210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a genomewide SNP association study involving 1,803 patients with urinary bladder cancer and 34,336 controls from Iceland and the Netherlands, and follow-up studies in 7 additional case-control groups (2,165 cases and 3,800 controls), <a href="#18" class="mim-tip-reference" title="Kiemeney, L. A., Thorlacius, S., Sulem, P., Geller, F., Aben, K. K. H., Stacey, S. N., Gudmundsson, J., Jakobsdottir, M., Bergthorsson, J. T., Sigurdsson, A., Blondal, T., Witjes, J. A., and 52 others. <strong>Sequence variant on 8q24 confers susceptibility to urinary bladder cancer.</strong> Nature Genet. 40: 1307-1311, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18794855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18794855</a>] [<a href="https://doi.org/10.1038/ng.229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18794855">Kiemeney et al. (2008)</a> found a strong association with allele T of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9642880;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs9642880</a> on chromosome 8q24, 30 kb upstream of the MYC gene (<a href="/entry/190080">190080</a>) (odds ratio = 1.22; p = 9.34 x 10(-12)). <a href="#18" class="mim-tip-reference" title="Kiemeney, L. A., Thorlacius, S., Sulem, P., Geller, F., Aben, K. K. H., Stacey, S. N., Gudmundsson, J., Jakobsdottir, M., Bergthorsson, J. T., Sigurdsson, A., Blondal, T., Witjes, J. A., and 52 others. <strong>Sequence variant on 8q24 confers susceptibility to urinary bladder cancer.</strong> Nature Genet. 40: 1307-1311, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18794855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18794855</a>] [<a href="https://doi.org/10.1038/ng.229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18794855">Kiemeney et al. (2008)</a> estimated that approximately 20% of individuals of European ancestry are homozygous for the T allele, and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between bladder cancer and other 8q24 variants previously associated with prostate, colorectal, and breast cancers. A weaker signal was observed with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs710521;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs710521</a> located near TP63 (<a href="/entry/603273">603273</a>) on chromosome 3q28 (odds ratio = 1.19; p = 1.15 x 10(-7)). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18794855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 follow-up study of bladder cancer (<a href="#18" class="mim-tip-reference" title="Kiemeney, L. A., Thorlacius, S., Sulem, P., Geller, F., Aben, K. K. H., Stacey, S. N., Gudmundsson, J., Jakobsdottir, M., Bergthorsson, J. T., Sigurdsson, A., Blondal, T., Witjes, J. A., and 52 others. <strong>Sequence variant on 8q24 confers susceptibility to urinary bladder cancer.</strong> Nature Genet. 40: 1307-1311, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18794855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18794855</a>] [<a href="https://doi.org/10.1038/ng.229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18794855">Kiemeney et al., 2008</a>) using several European case-control sample sets comprising 4,739 patients and 45,549 controls, <a href="#17" class="mim-tip-reference" title="Kiemeney, L. A., Sulem, P., Besenbacher, S., Vermeulen, S. H., Sigurdsson, A., Thorleifsson, G., Gudbjartsson, D. F., Stacey, S. N., Gudmundsson, J., Zanon, C., Kostic, J., Masson, G., and 61 others. <strong>A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.</strong> Nature Genet. 42: 415-419, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20348956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20348956</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20348956[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20348956">Kiemeney et al. (2010)</a> found a significant association between the T allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs798766;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs798766</a> in intron 5 of the TACC3 gene (<a href="/entry/605303">605303</a>) on chromosome 4p16.3 and bladder cancer (odds ratio of 1.24, p = 9.9 x 10(-12)). TACC3 is located 70 kb from FGFR3 (<a href="/entry/134934">134934</a>). The SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs798766;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs798766</a> showed a stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease, and was associated with higher risk of recurrence in low-grade stage Ta tumors. Moreover, the frequency of the T allele was higher in stage Ta (noninvasive) tumors that had an activating mutation in the FGFR3 gene than in Ta tumors with wildtype FGFR3. Further cellular studies suggested that the T allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs798766;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs798766</a> may influence expression of FGFR3. The results suggested a link between germline variants, somatic mutations of FGFR3, and risk of urinary bladder cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20348956+18794855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Analysis of LOH at 11p13, a region containing the Wilms tumor suppressor gene (WT1; <a href="/entry/607102">607102</a>), showed deletion at the CAT locus (<a href="/entry/115500">115500</a>) in 13 of 18 bladder cancers (72%), at the WT1 locus in 7 of 14 (50%), and at the FSHB locus (<a href="/entry/136530">136530</a>) in 6 of 16 (38%).</p><p>See <a href="/entry/190020#0001">190020.0001</a> for a somatic mutation identified in the HRAS oncogene in a bladder carcinoma.</p><p>See <a href="/entry/190070#0002">190070.0002</a> for a somatic mutation identified in the KRAS oncogene in a bladder carcinoma.</p><p>See <a href="/entry/614041#0009">614041.0009</a> for a somatic mutation identified in the RB1 gene in a bladder carcinoma.</p><p><a href="#27" class="mim-tip-reference" title="Risch, A., Wallace, D. M. A., Bathers, S., Sim, E. <strong>Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer.</strong> Hum. Molec. Genet. 4: 231-236, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757072</a>] [<a href="https://doi.org/10.1093/hmg/4.2.231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7757072">Risch et al. (1995)</a> demonstrated that the slow N-acetylation genotype (NAT2; <a href="/entry/612182">612182</a>) is a susceptibility factor in occupational and smoking-related bladder cancer. Employing PCR-based genotyping, they investigated NAT2 type among 189 Caucasian bladder cancer patients attending a clinic in Birmingham, U.K. The results were compared to those from an age-matched nonmalignant Caucasian control population from the same region. <a href="#27" class="mim-tip-reference" title="Risch, A., Wallace, D. M. A., Bathers, S., Sim, E. <strong>Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer.</strong> Hum. Molec. Genet. 4: 231-236, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757072</a>] [<a href="https://doi.org/10.1093/hmg/4.2.231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7757072">Risch et al. (1995)</a> found a significant excess of genotypic slow acetylators in patients exposed to arylamines as a result of their occupation or cigarette use. A higher proportion of slow acetylators was also found in most bladder cancer patients without identified exposure to arylamines when compared to the nonmalignant controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7757072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Hruban, R. H., van der Riet, P., Erozan, Y. S., Sidransky, D. <strong>Molecular biology and the early detection of carcinoma of the bladder: the case of Hubert H. Humphrey.</strong> New Eng. J. Med. 330: 1276-1278, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7993407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7993407</a>] [<a href="https://doi.org/10.1056/NEJM199405053301805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7993407">Hruban et al. (1994)</a> did a retrospective molecular genetic analysis of the bladder carcinoma that was the cause of death in the case of Hubert H. Humphrey (1911-1978), U.S. senator and vice president. In 1967, hematuria led to a diagnosis of chronic proliferative cystitis. Although urine cytology at that time was thought by one prominent cytopathologist to be diagnostic of carcinoma, a diagnosis of infiltrating carcinoma of the bladder was not made until August 1976. <a href="#13" class="mim-tip-reference" title="Hruban, R. H., van der Riet, P., Erozan, Y. S., Sidransky, D. <strong>Molecular biology and the early detection of carcinoma of the bladder: the case of Hubert H. Humphrey.</strong> New Eng. J. Med. 330: 1276-1278, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7993407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7993407</a>] [<a href="https://doi.org/10.1056/NEJM199405053301805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7993407">Hruban et al. (1994)</a> analyzed both the invasive bladder carcinoma resected in 1976 and the filters prepared from urine in 1967. Both showed a transversion from adenine to thymine in codon 227, creating a cryptic splice site in exon 7 of the p53 gene (<a href="/entry/191170">191170</a>). The mutation resulted in the loss of several amino acids and in the production of a shortened, mutant p53 protein. This mutation was not present in nonneoplastic tissue of the resected bladder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7993407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#4" class="mim-tip-reference" title="Cappellen, D., De Oliveira, C., Ricol, D., Gil Diez de Medina, S., Bourdin, J., Sastre-Garau, X., Chopin, D., Thiery, J. P., Radvanyi, F. <strong>Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. (Letter)</strong> Nature Genet. 23: 18-20, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10471491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10471491</a>] [<a href="https://doi.org/10.1038/12615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10471491">Cappellen et al. (1999)</a> found expression of a constitutively activated FGFR3 in a large proportion of 2 common epithelial cancers, bladder cancer and cervical cancer (<a href="/entry/603956">603956</a>). The most frequent FGFR3 somatic mutation in epithelial tumors was ser249 to cys (<a href="/entry/134934#0013">134934.0013</a>), affecting 5 of 9 bladder cancers and 3 of 3 cervical cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10471491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 studies for bladder cancer predisposition, <a href="#35" class="mim-tip-reference" title="Wu, X., Gu, J., Grossman, H. B., Amos, C. I., Etzel, C., Huang, M., Zhang, Q., Millikan, R. E., Lerner, S., Dinney, C. P., Spitz, M. R. <strong>Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes.</strong> Am. J. Hum. Genet. 78: 464-479, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16465622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16465622</a>] [<a href="https://doi.org/10.1086/500848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16465622">Wu et al. (2006)</a> applied a multigenic approach using a comprehensive panel of 44 selected polymorphisms in 2 pathways, DNA repair and cell cycle control, and, to evaluate higher order gene-gene interactions, classification and regression tree (CART) analysis. This hospital-based case-control study involved 696 white patients newly diagnosed with bladder cancer and 629 unaffected white controls. Individually, only the asp312-to-asn polymorphism of the XPD gene (<a href="/entry/126340">126340</a>), the lys820-to-arg polymorphism of the RAG1 gene (<a href="/entry/179615">179615</a>), and an intronic SNP of the p53 gene (<a href="/entry/191170">191170</a>) exhibited statistically significant main effects. However, <a href="#35" class="mim-tip-reference" title="Wu, X., Gu, J., Grossman, H. B., Amos, C. I., Etzel, C., Huang, M., Zhang, Q., Millikan, R. E., Lerner, S., Dinney, C. P., Spitz, M. R. <strong>Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes.</strong> Am. J. Hum. Genet. 78: 464-479, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16465622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16465622</a>] [<a href="https://doi.org/10.1086/500848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16465622">Wu et al. (2006)</a> found a significant gene dosage effect for increasing numbers of potential high risk alleles in DNA repair and cell cycle pathways separately and combined. In addition, they found that smoking had a significant multiplicative interaction with SNPs in the combined DNA repair and cell cycle control pathways (P less than 0.01). All genetic effects were evident only in 'ever smokers' (persons who had smoked more than 100 cigarettes) and not in 'never smokers.' Moreover, subgroups identified with higher cancer risk also exhibited higher levels of induced genetic damage than did subgroups with lower risk. There was a significant trend of higher numbers of bleomycin- and benzo[a]pyrine diol-epoxide (BPDE)-induced chromatid breaks (by mutagen sensitivity assay) and DNA damage (by comet assay) for individuals in higher risk subgroups among cases of bladder cancer in smokers. Thus, higher order gene-gene and gene-smoking interactions included SNPs that modulated repair and resulted in diminished DNA repair capacity. This study confirmed the importance of taking a multigene pathway-based approach to risk assessment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16465622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Fliss, M. S., Usadel, H., Caballero, O. L., Wu, L., Buta, M. R., Eleff, S. M., Jen, J., Sidransky, D. <strong>Facile detection of mitochondrial DNA mutations in tumors and bodily fluids.</strong> Science 287: 2017-2019, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10720328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10720328</a>] [<a href="https://doi.org/10.1126/science.287.5460.2017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10720328">Fliss et al. (2000)</a> identified a somatic 21-bp deletion in the mitochondrial MTCYB gene in tumor tissue from a patient with bladder cancer. <a href="#5" class="mim-tip-reference" title="Dasgupta, S., Hoque, M. O., Upadhyay, S., Sidransky, D. <strong>Mitochondrial cytochrome B gene mutation promotes tumor growth in bladder cancer.</strong> Cancer Res. 68: 700-706, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18245469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18245469</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-07-5532" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18245469">Dasgupta et al. (2008)</a> found that overexpression of the deletion identified by <a href="#8" class="mim-tip-reference" title="Fliss, M. S., Usadel, H., Caballero, O. L., Wu, L., Buta, M. R., Eleff, S. M., Jen, J., Sidransky, D. <strong>Facile detection of mitochondrial DNA mutations in tumors and bodily fluids.</strong> Science 287: 2017-2019, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10720328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10720328</a>] [<a href="https://doi.org/10.1126/science.287.5460.2017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10720328">Fliss et al. (2000)</a> in murine bladder cancer cells resulted in increased tumor growth and an invasive phenotype in vitro and after injection into mice. Increased tumor growth was associated with shifts toward glycolysis and production of reactive oxygen species (ROS). Rapid cell cycle progression was associated with upregulation of the NFKB (<a href="/entry/164011">164011</a>) signaling pathway, and inhibition of ROS or NFKB diminished tumor growth in vitro. Transfection of the 21-bp deletion into human uroepithelial cells resulted in similar effects. The findings suggested that mitochondrial mutations may contribute to tumor growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18245469+10720328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="van der Post, R. S., Kiemeney, L. A., Ligtenberg, M. J. L., Witjes, J. A., Hulsbergen-van de Kaa, C. A., Bodmer, D., Schaap, L., Kets, C. M., van Krieken, J. H. J. M., Hoogerbrugge, N. <strong>Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers.</strong> J. Med. Genet. 47: 464-470, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20591884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20591884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20591884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2010.076992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20591884">Van der Post et al. (2010)</a> used a questionnaire-based survey to ascertain the risk of urogenital cancer in 95 families with HNPCC (see, e.g., <a href="/entry/120435">120435</a>). Bladder cancer was diagnosed in 21 patients (90% men) from 19 families; 15 had mutations in the MSH2 gene (<a href="/entry/609309">609309</a>). Men carrying an MSH2 mutation and their first degree relatives had a cumulative risk by age 70 of 12.3% for bladder cancer and 5.9% for upper urinary tract cancer. <a href="#34" class="mim-tip-reference" title="van der Post, R. S., Kiemeney, L. A., Ligtenberg, M. J. L., Witjes, J. A., Hulsbergen-van de Kaa, C. A., Bodmer, D., Schaap, L., Kets, C. M., van Krieken, J. H. J. M., Hoogerbrugge, N. <strong>Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers.</strong> J. Med. Genet. 47: 464-470, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20591884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20591884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20591884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2010.076992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20591884">Van der Post et al. (2010)</a> concluded that patients with Lynch syndrome, particularly those carrying MSH2 mutations, have an increased risk of urinary tract cancer, which may warrant surveillance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20591884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Gui, Y., Guo, G., Huang, Y., Hu, X., Tang, A., Gao, S., Wu, R., Chen, C., Li, X., Zhou, L., He, M., Li, Z., and 41 others. <strong>Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder.</strong> Nature Genet. 43: 875-878, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21822268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21822268</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21822268[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21822268">Gui et al. (2011)</a> sequenced the exomes of 9 individuals with TCC and screened all somatically mutated genes in a covalent set of 88 additional individuals with TCC with different tumor stages and grades. <a href="#11" class="mim-tip-reference" title="Gui, Y., Guo, G., Huang, Y., Hu, X., Tang, A., Gao, S., Wu, R., Chen, C., Li, X., Zhou, L., He, M., Li, Z., and 41 others. <strong>Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder.</strong> Nature Genet. 43: 875-878, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21822268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21822268</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21822268[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21822268">Gui et al. (2011)</a> discovered a variety of genes previously unknown to be mutated in TCC. Notably, they identified genetic aberrations of the chromatin remodeling genes UTX (<a href="/entry/300128">300128</a>), MLL (<a href="/entry/159555">159555</a>), MLL3 (<a href="/entry/606833">606833</a>), CREBBP (<a href="/entry/600140">600140</a>), EP300 (<a href="/entry/602700">602700</a>), NCOR1 (<a href="/entry/600849">600849</a>), ARID1A (<a href="/entry/603024">603024</a>), and CHD6 in 59% of 97 subjects with TCC. Of these genes, UTX was altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21822268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Solomon, D. A., Kim, J.-S., Bondaruk, J., Shariat, S. F., Wang, Z.-F., Elkahloun, A. G., Ozawa, T., Gerard, J., Zhuang, D., Zhang, S., Navai, N., Siefker-Radtke, A., and 13 others. <strong>Frequent truncating mutations of STAG2 in bladder cancer.</strong> Nature Genet. 45: 1428-1430, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24121789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24121789</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24121789[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24121789">Solomon et al. (2013)</a> reported the discovery of truncating mutations of STAG2 (<a href="/entry/300826">300826</a>), which regulates sister chromatid cohesion and segregation, in 36% of papillary noninvasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. <a href="#32" class="mim-tip-reference" title="Solomon, D. A., Kim, J.-S., Bondaruk, J., Shariat, S. F., Wang, Z.-F., Elkahloun, A. G., Ozawa, T., Gerard, J., Zhuang, D., Zhang, S., Navai, N., Siefker-Radtke, A., and 13 others. <strong>Frequent truncating mutations of STAG2 in bladder cancer.</strong> Nature Genet. 45: 1428-1430, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24121789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24121789</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24121789[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24121789">Solomon et al. (2013)</a> stated that their studies suggested that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24121789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Guo, G., Sun, X., Chen, C., Wu, S., Huang, P., Li, Z., Dean, M., Huang, Y., Jia, W., Zhou, Q., Tang, A., Yang, Z., and 44 others. <strong>Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation.</strong> Nature Genet. 45: 1459-1463, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24121792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24121792</a>] [<a href="https://doi.org/10.1038/ng.2798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24121792">Guo et al. (2013)</a> reported genomic analysis of transitional cell carcinoma (TCC) by both whole-genome and whole-exome sequencing in 99 individuals. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, <a href="#12" class="mim-tip-reference" title="Guo, G., Sun, X., Chen, C., Wu, S., Huang, P., Li, Z., Dean, M., Huang, Y., Jia, W., Zhou, Q., Tang, A., Yang, Z., and 44 others. <strong>Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation.</strong> Nature Genet. 45: 1459-1463, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24121792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24121792</a>] [<a href="https://doi.org/10.1038/ng.2798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24121792">Guo et al. (2013)</a> identified additional altered genes and pathways that were implicated in TCC. <a href="#12" class="mim-tip-reference" title="Guo, G., Sun, X., Chen, C., Wu, S., Huang, P., Li, Z., Dean, M., Huang, Y., Jia, W., Zhou, Q., Tang, A., Yang, Z., and 44 others. <strong>Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation.</strong> Nature Genet. 45: 1459-1463, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24121792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24121792</a>] [<a href="https://doi.org/10.1038/ng.2798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24121792">Guo et al. (2013)</a> discovered frequent alterations in STAG2 (<a href="/entry/300826">300826</a>) and ESPL1 (<a href="/entry/604143">604143</a>), both involved in the sister chromatid cohesion and segregation process. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the sister chromatid cohesion and segregation process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24121792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Balbas-Martinez, C., Sagrera, A., Carrillo-de-Santa-Pau, E., Earl, J., Marquez, M., Vazquez, M., Lapi, E., Castro-Giner, F., Beltran, S., Bayes, M., Carrato, A., Cigudosa, J. C., and 21 others. <strong>Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.</strong> Nature Genet. 45: 1464-1469, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24121791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24121791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24121791[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24121791">Balbas-Martinez et al. (2013)</a> found that STAG2 was significantly and commonly mutated or lost in urothelial bladder cancer, mainly in tumors of low stage or grade, and that its loss was associated with improved outcome. Loss of expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in nonexpressing cells led to reduced colony formation. <a href="#1" class="mim-tip-reference" title="Balbas-Martinez, C., Sagrera, A., Carrillo-de-Santa-Pau, E., Earl, J., Marquez, M., Vazquez, M., Lapi, E., Castro-Giner, F., Beltran, S., Bayes, M., Carrato, A., Cigudosa, J. C., and 21 others. <strong>Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.</strong> Nature Genet. 45: 1464-1469, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24121791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24121791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24121791[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24121791">Balbas-Martinez et al. (2013)</a> found that STAG2 is a novel urothelial bladder cancer tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24121791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Borah, S., Xi, L., Zaug, A. J., Powell, N. M., Dancik, G. M., Cohen, S. B., Costello, J. C., Theodorescu, D., Cech, T. R. <strong>TERT promoter mutations and telomerase reactivation in urothelial cancer.</strong> Science 347: 1006-1010, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722414</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722414[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1260200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25722414">Borah et al. (2015)</a> studied 23 human urothelial cancer cell lines and showed that point mutations in the TERT (<a href="/entry/187270">187270</a>) promoter correlate with higher levels of TERT mRNA, TERT protein, telomerase enzymatic activity, and telomere length. Although previous studies found no relation between TERT promoter mutations and urothelial cancer patient outcome, <a href="#3" class="mim-tip-reference" title="Borah, S., Xi, L., Zaug, A. J., Powell, N. M., Dancik, G. M., Cohen, S. B., Costello, J. C., Theodorescu, D., Cech, T. R. <strong>TERT promoter mutations and telomerase reactivation in urothelial cancer.</strong> Science 347: 1006-1010, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722414</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722414[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1260200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25722414">Borah et al. (2015)</a> found that elevated TERT mRNA expression strongly correlates with reduced disease-specific survival in 2 independent urothelial cancer patient cohorts (n = 35; n = 87). <a href="#3" class="mim-tip-reference" title="Borah, S., Xi, L., Zaug, A. J., Powell, N. M., Dancik, G. M., Cohen, S. B., Costello, J. C., Theodorescu, D., Cech, T. R. <strong>TERT promoter mutations and telomerase reactivation in urothelial cancer.</strong> Science 347: 1006-1010, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722414</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722414[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1260200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25722414">Borah et al. (2015)</a> concluded that their results suggested that high telomerase activity may be a better marker of aggressive urothelial cancer tumors than TERT promoter mutations alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25722414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#14" class="mim-tip-reference" title="Iyer, G. Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, M., Pirun, M., Sander, C., Socci, N. D., Ostrovnaya, I., Viale, A., Heguy, A., Peng, L., Chan, T. A., Bochner, B., Bajorin, D. F., Berger, M. F., Taylor, B. S., Solit, D. B. <strong>Genome sequencing identifies a basis for everolimus sensitivity.</strong> Science 338: 221 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22923433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22923433</a>] [<a href="https://doi.org/10.1126/science.1226344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22923433">Iyer et al. (2012)</a> studied the tumor genome of a patient with metastatic bladder cancer who achieved a durable (greater than 2 years) and ongoing complete response to everolimus, a drug targeting the mTORC1 complex (see <a href="/entry/601231">601231</a>). Whole genome sequencing of DNA derived from the primary tumor and blood identified a 2-bp deletion in the TSC1 (<a href="/entry/605284">605284</a>) gene resulting in a frameshift truncation, and a nonsense mutation in the NF2 (<a href="/entry/607379">607379</a>) gene. <a href="#14" class="mim-tip-reference" title="Iyer, G. Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, M., Pirun, M., Sander, C., Socci, N. D., Ostrovnaya, I., Viale, A., Heguy, A., Peng, L., Chan, T. A., Bochner, B., Bajorin, D. F., Berger, M. F., Taylor, B. S., Solit, D. B. <strong>Genome sequencing identifies a basis for everolimus sensitivity.</strong> Science 338: 221 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22923433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22923433</a>] [<a href="https://doi.org/10.1126/science.1226344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22923433">Iyer et al. (2012)</a> sequenced both genes in a second cohort of 96 high-grade bladder cancers and identified 5 additional somatic TSC1 mutations, whereas no additional NF2 mutations were detected. Subsequently, <a href="#14" class="mim-tip-reference" title="Iyer, G. Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, M., Pirun, M., Sander, C., Socci, N. D., Ostrovnaya, I., Viale, A., Heguy, A., Peng, L., Chan, T. A., Bochner, B., Bajorin, D. F., Berger, M. F., Taylor, B. S., Solit, D. B. <strong>Genome sequencing identifies a basis for everolimus sensitivity.</strong> Science 338: 221 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22923433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22923433</a>] [<a href="https://doi.org/10.1126/science.1226344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22923433">Iyer et al. (2012)</a> explored whether TSC1 mutation is a biomarker of clinical benefit from everolimus therapy in bladder cancer, and studied 13 additional bladder cancer patients treated with everolimus. Three additional tumors harbored nonsense mutations in TSC1, including 2 patients who had minor responses to everolimus (17% and 24% tumor regression, respectively). Tumors from 8 of the 9 patients who showed disease progression were TSC1 wildtype. Patients with TSC1-mutant tumors remained on everolimus longer than those with wildtype tumors (7.7 vs 2.0 months, p = 0.004) with a significant improvement in time to recurrence (4.1 vs 1.8 months; hazard ratio = 18.5, 95% confidence interval 2.1 to 162, p = 0.001). <a href="#14" class="mim-tip-reference" title="Iyer, G. Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, M., Pirun, M., Sander, C., Socci, N. D., Ostrovnaya, I., Viale, A., Heguy, A., Peng, L., Chan, T. A., Bochner, B., Bajorin, D. F., Berger, M. F., Taylor, B. S., Solit, D. B. <strong>Genome sequencing identifies a basis for everolimus sensitivity.</strong> Science 338: 221 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22923433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22923433</a>] [<a href="https://doi.org/10.1126/science.1226344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22923433">Iyer et al. (2012)</a> concluded that mTORC1-directed therapies may be most effective in cancer patients whose tumors harbor TSC1 somatic mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22923433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Powles, T., Eder, J. P., Fine, G. D., Braiteh, F. S., Loriot, Y., Cruz, C., Bellmunt, J., Burris, H. A., Petrylak, D. P., Teng, S., Shen, X., Boyd, Z., Hegde, P. S., Chen, D. S., Vogelzang, N. J. <strong>MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.</strong> Nature 515: 558-562, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25428503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25428503</a>] [<a href="https://doi.org/10.1038/nature13904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25428503">Powles et al. (2014)</a> examined the anti-PDL1 (<a href="/entry/605402">605402</a>) antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of urothelial bladder cancer (UBC). MPDL3280A is a high-affinity engineered human anti-PDL1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PDL1 with PD1 (PDCD1; <a href="/entry/600244">600244</a>) and B7.1 (CD80; <a href="/entry/112203">112203</a>). Because PDL1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PDL1. <a href="#26" class="mim-tip-reference" title="Powles, T., Eder, J. P., Fine, G. D., Braiteh, F. S., Loriot, Y., Cruz, C., Bellmunt, J., Burris, H. A., Petrylak, D. P., Teng, S., Shen, X., Boyd, Z., Hegde, P. S., Chen, D. S., Vogelzang, N. J. <strong>MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.</strong> Nature 515: 558-562, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25428503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25428503</a>] [<a href="https://doi.org/10.1038/nature13904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25428503">Powles et al. (2014)</a> found that treatment with MPDL3280A resulted in rapid responses in metastatic UBC, with many occurring at the time of the first response assessment (6 weeks). Nearly all responses were ongoing at the data cutoff. In a phase I expansion study, <a href="#26" class="mim-tip-reference" title="Powles, T., Eder, J. P., Fine, G. D., Braiteh, F. S., Loriot, Y., Cruz, C., Bellmunt, J., Burris, H. A., Petrylak, D. P., Teng, S., Shen, X., Boyd, Z., Hegde, P. S., Chen, D. S., Vogelzang, N. J. <strong>MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.</strong> Nature 515: 558-562, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25428503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25428503</a>] [<a href="https://doi.org/10.1038/nature13904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25428503">Powles et al. (2014)</a> showed that tumors expressing PDL1-positive tumor-infiltrating immune cells had particularly high response rates. MPDL3280A has a favorable toxicity profile, including a lack of renal toxicity, which suggested that it might be better tolerated by patients with UBC than chemotherapy. Patients with UBC tend to be older and to have a higher incidence of renal impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25428503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#Krontiris1981" class="mim-tip-reference" title="Krontiris, T. G., Cooper, G. M. <strong>Transforming activity of human tumor DNAs.</strong> Proc. Nat. Acad. Sci. 78: 1181-1184, 1981.">Krontiris and Cooper (1981)</a>; <a href="#Leklem1976" class="mim-tip-reference" title="Leklem, J. E., Brown, R. R. <strong>Abnormal tryptophan metabolism in a family with a history of bladder cancer.</strong> J. Nat. Cancer Inst. 56: 1101-1104, 1976.">Leklem and Brown (1976)</a>; <a href="#Lynch1979" class="mim-tip-reference" title="Lynch, H. T., Walzak, M. P., Fried, R., Domina, A. H., Lynch, J. F. <strong>Familial factors in bladder carcinoma.</strong> J. Urol. 122: 458-461, 1979.">Lynch et al.
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(1979)</a>; <a href="#Mahboubi1981" class="mim-tip-reference" title="Mahboubi, A. O., Ahlvin, R. C., Mahboubi, E. O. <strong>Familial aggregation of urothelial carcinoma.</strong> J. Urol. 126: 691-692, 1981.">Mahboubi et al. (1981)</a>
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Balbas-Martinez, C., Sagrera, A., Carrillo-de-Santa-Pau, E., Earl, J., Marquez, M., Vazquez, M., Lapi, E., Castro-Giner, F., Beltran, S., Bayes, M., Carrato, A., Cigudosa, J. C., and 21 others.
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<strong>Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.</strong>
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Nature Genet. 45: 1464-1469, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24121791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24121791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24121791[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=24121791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2799" target="_blank">Full Text</a>]
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Bishop, J. M.
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<strong>Oncogenes.</strong>
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Sci. Am. 246(3): 80-92, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6281879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6281879</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6281879" 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/scientificamerican0382-80" target="_blank">Full Text</a>]
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Borah, S., Xi, L., Zaug, A. J., Powell, N. M., Dancik, G. M., Cohen, S. B., Costello, J. C., Theodorescu, D., Cech, T. R.
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<strong>TERT promoter mutations and telomerase reactivation in urothelial cancer.</strong>
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Science 347: 1006-1010, 2015.
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[<a href="https://doi.org/10.1016/s0022-5347(17)59540-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature13904" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/4.2.231" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/290261a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00217771" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199203123261104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.2800" target="_blank">Full Text</a>]
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<a id="van der Post2010" class="mim-anchor"></a>
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van der Post, R. S., Kiemeney, L. A., Ligtenberg, M. J. L., Witjes, J. A., Hulsbergen-van de Kaa, C. A., Bodmer, D., Schaap, L., Kets, C. M., van Krieken, J. H. J. M., Hoogerbrugge, N.
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[<a href="https://doi.org/10.1136/jmg.2010.076992" target="_blank">Full Text</a>]
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<a id="Wu2006" class="mim-anchor"></a>
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Wu, X., Gu, J., Grossman, H. B., Amos, C. I., Etzel, C., Huang, M., Zhang, Q., Millikan, R. E., Lerner, S., Dinney, C. P., Spitz, M. R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16465622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16465622</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16465622" 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/10.1086/500848" target="_blank">Full Text</a>]
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<br />
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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 : 02/01/2016
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<span class="mim-text-font">
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Ada Hamosh - updated : 1/13/2015<br>Ada Hamosh - updated : 1/9/2014<br>Ada Hamosh - updated : 11/5/2012<br>Ada Hamosh - updated : 10/7/2011<br>Cassandra L. Kniffin - updated : 12/3/2010<br>Cassandra L. Kniffin - updated : 5/10/2010<br>Cassandra L. Kniffin - updated : 11/19/2008<br>Cassandra L. Kniffin - updated : 10/23/2008<br>Victor A. McKusick - updated : 2/20/2006<br>Victor A. McKusick - updated : 12/31/2002<br>Victor A. McKusick - updated : 12/10/2002<br>Victor A. McKusick - updated : 1/12/2000<br>Victor A. McKusick - updated : 6/21/1997
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Creation Date:
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Victor A. McKusick : 6/4/1986
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 02/01/2016
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alopez : 1/13/2015<br>alopez : 1/13/2015<br>alopez : 1/9/2014<br>alopez : 11/5/2012<br>alopez : 11/5/2012<br>alopez : 10/13/2011<br>terry : 10/7/2011<br>carol : 6/17/2011<br>wwang : 1/4/2011<br>ckniffin : 12/3/2010<br>alopez : 5/12/2010<br>ckniffin : 5/10/2010<br>ckniffin : 5/10/2010<br>terry : 6/3/2009<br>alopez : 11/21/2008<br>ckniffin : 11/19/2008<br>wwang : 10/24/2008<br>ckniffin : 10/23/2008<br>ckniffin : 10/23/2008<br>carol : 8/28/2008<br>ckniffin : 3/1/2007<br>alopez : 2/22/2006<br>terry : 2/20/2006<br>alopez : 1/8/2003<br>carol : 1/3/2003<br>terry : 12/31/2002<br>alopez : 12/10/2002<br>terry : 12/10/2002<br>ckniffin : 8/26/2002<br>mgross : 1/31/2000<br>terry : 1/12/2000<br>terry : 6/24/1997<br>terry : 6/21/1997<br>terry : 10/22/1996<br>mark : 3/31/1995<br>carol : 9/12/1994<br>davew : 6/8/1994<br>mimadm : 4/9/1994<br>carol : 8/18/1993<br>carol : 5/11/1992
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<span class="mim-font">
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<strong>#</strong> 109800
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<h3>
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BLADDER CANCER
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<strong>SNOMEDCT:</strong> 399326009;
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<strong>ICD10CM:</strong> C67, C67.9;
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<strong>ICD9CM:</strong> 188, 188.9;
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<strong>DO:</strong> 11054;
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<h4>
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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4p16.3
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Bladder cancer, somatic
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109800
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3
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FGFR3
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134934
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11p15.5
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Bladder cancer, somatic
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109800
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3
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HRAS
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190020
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12p12.1
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Bladder cancer, somatic
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109800
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3
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KRAS
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190070
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13q14.2
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Bladder cancer, somatic
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109800
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3
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RB1
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614041
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</h4>
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<p>A number sign (#) is used with this entry because bladder cancer is a complex disorder with both genetic and environmental influences. Somatic mutations in several genes, e.g., HRAS (190020), KRAS2 (190070), RB1 (614041), and FGFR3 (134934), have been implicated in bladder carcinogenesis. See Bishop (1982) for a discussion of oncogenes. </p>
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<h4>
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<strong>Clinical Features</strong>
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<p>Patients with cancer of the urinary bladder often present with multiple tumors appearing at different times and at different sites in the bladder. This observation had been attributed to a 'field defect' in the bladder that allowed the independent transformation of epithelial cells at a number of sites. Sidransky et al. (1992) tested this hypothesis with molecular genetic techniques and concluded that in fact multiple bladder tumors are of clonal origin. A number of bladder tumors can arise from the uncontrolled spread of a single transformed cell. These tumors can then grow independently with variable subsequent genetic alterations. </p><p>Dyrskjot et al. (2003) reported the identification of clinically relevant subclasses of bladder carcinoma using expression microarray analysis of 40 well-characterized bladder tumors. Gene expression profiles characterizing each stage and subtype identified their biologic properties, producing potential targets for therapy. </p>
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<h4>
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<strong>Inheritance</strong>
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<p>Fraumeni and Thomas (1967) observed affected father and 3 sons. McKusick (1972) encountered 2 instances of affected father and son at the Johns Hopkins Hospital. McCullough et al. (1975) found transitional cell carcinoma (TCC) in 6 persons in 3 sibships of 2 generations of a kindred. </p><p>In a review of case reports and epidemiologic studies in the literature, Kiemeney and Schoenberg (1996) concluded that first-degree relatives have an increased risk for TCC by a factor of 2. Familial clustering of smoking did not appear to be the cause of this increased risk. </p><p>In Iceland, Kiemeney et al. (1997) studied the first- to third-degree relatives of 190 patients with bladder, ureter, or renal pelvis TCC diagnosed between 1983 and 1992. In 41 of the 190 pedigrees, at least 1 relative had TCC of the urinary tract. Of the probands, 38 had only 1 and 3 had 2 affected relatives. The prevalence of family history of TCC was 3% in first-degree and 10% in first- or second-degree relatives. The risk of TCC among all relatives was slightly elevated, the observed-to-expected ratio being greater among second- and third-degree relatives than among first-degree relatives. Kiemeney et al. (1997) concluded that the greater risk among distant relatives argues against the existence of a hereditary subtype of bladder TCC, at least in the founder population of Iceland. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>Goldfarb et al. (1982) studied the DNA from T24, a cell line derived from a human bladder carcinoma, which can induce the morphologic transformation of nonmalignant cells. The gene responsible for this transformation was cloned by techniques of gene rescue: it was shown to be human in origin and less than 5 kb long. By Southern blot analysis of human-rodent hybrid cell DNA, de Martinville et al. (1983) found that the cellular homolog of the transforming DNA sequence isolated from the bladder carcinoma line EJ is located on the short arm of chromosome 11, which contains sequences homologous to the HRAS (190020) oncogene. No evidence of gene amplification was found. These workers also found karyologically 'a complex rearrangement of the short arm in two of the four copies of chromosome 11 present in this heteroploid cell line' (EJ). Shih et al. (1981) found that DNA from mouse and rabbit bladder cancers as well as from the human bladder cancer cell line EJ induced foci of transformed cells when applied to monolayer cultures of NIH3T3 cells. </p><p>Deletions involving chromosome 9 represent the most frequent genetic change identified in bladder tumors. Several independent studies had reported overall deletion frequencies of 50 to 70% in large series of tumors (see review by Sandberg, 2002). It was of particular interest that these deletions were present at similar frequency in bladder tumors of all grades and stages (Tsai et al., 1990). This finding of chromosome 9 deletions as the sole genetic change in many low-grade, early-stage tumors suggests that it may represent an early or initiating genetic event. Keen and Knowles (1994) used a panel of 22 highly informative microsatellite markers, evenly distributed along chromosome 9, to analyze LOH in 95 cases of primary TCC of the bladder. In 49 tumors (53%), LOH was demonstrated at one or more loci. Of these 49, 30 had LOH at all informative loci, indicating probable monosomy 9. Subchromosomal deletions were found in 19 tumors (22%), 5 of 9p only, 9 of 9q only, and 5 of both 9p and 9q with a clear region of retention of heterozygosity between. The patterns of LOH in these tumors indicated a common region of deletion on 9p between D9S126 (9p21) and the interferon-alpha cluster (IFNA; 147660) located also at 9p21. A single tumor showed a second site of deletion on 9p telomeric to IFNA, indicating the possible existence of 2 target genes on 9p. All deletions of 9q were large, with a common region of deletion between D9S15 (9q13-q21.1) and D9S60 (9q33-q34.1). The results provided evidence for the simultaneous involvement of distinct suppressor loci on 9p and 9q in bladder carcinoma. </p><p>In a study of loss of heterozygosity (LOH), Shipman et al. (1993) found no evidence of deletion at 17p13, the region known to contain the p53 tumor suppressor gene (TP53; 191170). </p><p>In a genomewide SNP association study involving 1,803 patients with urinary bladder cancer and 34,336 controls from Iceland and the Netherlands, and follow-up studies in 7 additional case-control groups (2,165 cases and 3,800 controls), Kiemeney et al. (2008) found a strong association with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of the MYC gene (190080) (odds ratio = 1.22; p = 9.34 x 10(-12)). Kiemeney et al. (2008) estimated that approximately 20% of individuals of European ancestry are homozygous for the T allele, and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between bladder cancer and other 8q24 variants previously associated with prostate, colorectal, and breast cancers. A weaker signal was observed with rs710521 located near TP63 (603273) on chromosome 3q28 (odds ratio = 1.19; p = 1.15 x 10(-7)). </p><p>In a follow-up study of bladder cancer (Kiemeney et al., 2008) using several European case-control sample sets comprising 4,739 patients and 45,549 controls, Kiemeney et al. (2010) found a significant association between the T allele of rs798766 in intron 5 of the TACC3 gene (605303) on chromosome 4p16.3 and bladder cancer (odds ratio of 1.24, p = 9.9 x 10(-12)). TACC3 is located 70 kb from FGFR3 (134934). The SNP rs798766 showed a stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease, and was associated with higher risk of recurrence in low-grade stage Ta tumors. Moreover, the frequency of the T allele was higher in stage Ta (noninvasive) tumors that had an activating mutation in the FGFR3 gene than in Ta tumors with wildtype FGFR3. Further cellular studies suggested that the T allele of rs798766 may influence expression of FGFR3. The results suggested a link between germline variants, somatic mutations of FGFR3, and risk of urinary bladder cancer. </p>
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<strong>Molecular Genetics</strong>
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<p>Analysis of LOH at 11p13, a region containing the Wilms tumor suppressor gene (WT1; 607102), showed deletion at the CAT locus (115500) in 13 of 18 bladder cancers (72%), at the WT1 locus in 7 of 14 (50%), and at the FSHB locus (136530) in 6 of 16 (38%).</p><p>See 190020.0001 for a somatic mutation identified in the HRAS oncogene in a bladder carcinoma.</p><p>See 190070.0002 for a somatic mutation identified in the KRAS oncogene in a bladder carcinoma.</p><p>See 614041.0009 for a somatic mutation identified in the RB1 gene in a bladder carcinoma.</p><p>Risch et al. (1995) demonstrated that the slow N-acetylation genotype (NAT2; 612182) is a susceptibility factor in occupational and smoking-related bladder cancer. Employing PCR-based genotyping, they investigated NAT2 type among 189 Caucasian bladder cancer patients attending a clinic in Birmingham, U.K. The results were compared to those from an age-matched nonmalignant Caucasian control population from the same region. Risch et al. (1995) found a significant excess of genotypic slow acetylators in patients exposed to arylamines as a result of their occupation or cigarette use. A higher proportion of slow acetylators was also found in most bladder cancer patients without identified exposure to arylamines when compared to the nonmalignant controls. </p><p>Hruban et al. (1994) did a retrospective molecular genetic analysis of the bladder carcinoma that was the cause of death in the case of Hubert H. Humphrey (1911-1978), U.S. senator and vice president. In 1967, hematuria led to a diagnosis of chronic proliferative cystitis. Although urine cytology at that time was thought by one prominent cytopathologist to be diagnostic of carcinoma, a diagnosis of infiltrating carcinoma of the bladder was not made until August 1976. Hruban et al. (1994) analyzed both the invasive bladder carcinoma resected in 1976 and the filters prepared from urine in 1967. Both showed a transversion from adenine to thymine in codon 227, creating a cryptic splice site in exon 7 of the p53 gene (191170). The mutation resulted in the loss of several amino acids and in the production of a shortened, mutant p53 protein. This mutation was not present in nonneoplastic tissue of the resected bladder. </p><p>Cappellen et al. (1999) found expression of a constitutively activated FGFR3 in a large proportion of 2 common epithelial cancers, bladder cancer and cervical cancer (603956). The most frequent FGFR3 somatic mutation in epithelial tumors was ser249 to cys (134934.0013), affecting 5 of 9 bladder cancers and 3 of 3 cervical cancers. </p><p>In studies for bladder cancer predisposition, Wu et al. (2006) applied a multigenic approach using a comprehensive panel of 44 selected polymorphisms in 2 pathways, DNA repair and cell cycle control, and, to evaluate higher order gene-gene interactions, classification and regression tree (CART) analysis. This hospital-based case-control study involved 696 white patients newly diagnosed with bladder cancer and 629 unaffected white controls. Individually, only the asp312-to-asn polymorphism of the XPD gene (126340), the lys820-to-arg polymorphism of the RAG1 gene (179615), and an intronic SNP of the p53 gene (191170) exhibited statistically significant main effects. However, Wu et al. (2006) found a significant gene dosage effect for increasing numbers of potential high risk alleles in DNA repair and cell cycle pathways separately and combined. In addition, they found that smoking had a significant multiplicative interaction with SNPs in the combined DNA repair and cell cycle control pathways (P less than 0.01). All genetic effects were evident only in 'ever smokers' (persons who had smoked more than 100 cigarettes) and not in 'never smokers.' Moreover, subgroups identified with higher cancer risk also exhibited higher levels of induced genetic damage than did subgroups with lower risk. There was a significant trend of higher numbers of bleomycin- and benzo[a]pyrine diol-epoxide (BPDE)-induced chromatid breaks (by mutagen sensitivity assay) and DNA damage (by comet assay) for individuals in higher risk subgroups among cases of bladder cancer in smokers. Thus, higher order gene-gene and gene-smoking interactions included SNPs that modulated repair and resulted in diminished DNA repair capacity. This study confirmed the importance of taking a multigene pathway-based approach to risk assessment. </p><p>Fliss et al. (2000) identified a somatic 21-bp deletion in the mitochondrial MTCYB gene in tumor tissue from a patient with bladder cancer. Dasgupta et al. (2008) found that overexpression of the deletion identified by Fliss et al. (2000) in murine bladder cancer cells resulted in increased tumor growth and an invasive phenotype in vitro and after injection into mice. Increased tumor growth was associated with shifts toward glycolysis and production of reactive oxygen species (ROS). Rapid cell cycle progression was associated with upregulation of the NFKB (164011) signaling pathway, and inhibition of ROS or NFKB diminished tumor growth in vitro. Transfection of the 21-bp deletion into human uroepithelial cells resulted in similar effects. The findings suggested that mitochondrial mutations may contribute to tumor growth. </p><p>Van der Post et al. (2010) used a questionnaire-based survey to ascertain the risk of urogenital cancer in 95 families with HNPCC (see, e.g., 120435). Bladder cancer was diagnosed in 21 patients (90% men) from 19 families; 15 had mutations in the MSH2 gene (609309). Men carrying an MSH2 mutation and their first degree relatives had a cumulative risk by age 70 of 12.3% for bladder cancer and 5.9% for upper urinary tract cancer. Van der Post et al. (2010) concluded that patients with Lynch syndrome, particularly those carrying MSH2 mutations, have an increased risk of urinary tract cancer, which may warrant surveillance. </p><p>Gui et al. (2011) sequenced the exomes of 9 individuals with TCC and screened all somatically mutated genes in a covalent set of 88 additional individuals with TCC with different tumor stages and grades. Gui et al. (2011) discovered a variety of genes previously unknown to be mutated in TCC. Notably, they identified genetic aberrations of the chromatin remodeling genes UTX (300128), MLL (159555), MLL3 (606833), CREBBP (600140), EP300 (602700), NCOR1 (600849), ARID1A (603024), and CHD6 in 59% of 97 subjects with TCC. Of these genes, UTX was altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. </p><p>Solomon et al. (2013) reported the discovery of truncating mutations of STAG2 (300826), which regulates sister chromatid cohesion and segregation, in 36% of papillary noninvasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Solomon et al. (2013) stated that their studies suggested that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. </p><p>Guo et al. (2013) reported genomic analysis of transitional cell carcinoma (TCC) by both whole-genome and whole-exome sequencing in 99 individuals. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, Guo et al. (2013) identified additional altered genes and pathways that were implicated in TCC. Guo et al. (2013) discovered frequent alterations in STAG2 (300826) and ESPL1 (604143), both involved in the sister chromatid cohesion and segregation process. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the sister chromatid cohesion and segregation process. </p><p>Balbas-Martinez et al. (2013) found that STAG2 was significantly and commonly mutated or lost in urothelial bladder cancer, mainly in tumors of low stage or grade, and that its loss was associated with improved outcome. Loss of expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in nonexpressing cells led to reduced colony formation. Balbas-Martinez et al. (2013) found that STAG2 is a novel urothelial bladder cancer tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy. </p><p>Borah et al. (2015) studied 23 human urothelial cancer cell lines and showed that point mutations in the TERT (187270) promoter correlate with higher levels of TERT mRNA, TERT protein, telomerase enzymatic activity, and telomere length. Although previous studies found no relation between TERT promoter mutations and urothelial cancer patient outcome, Borah et al. (2015) found that elevated TERT mRNA expression strongly correlates with reduced disease-specific survival in 2 independent urothelial cancer patient cohorts (n = 35; n = 87). Borah et al. (2015) concluded that their results suggested that high telomerase activity may be a better marker of aggressive urothelial cancer tumors than TERT promoter mutations alone. </p>
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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>Iyer et al. (2012) studied the tumor genome of a patient with metastatic bladder cancer who achieved a durable (greater than 2 years) and ongoing complete response to everolimus, a drug targeting the mTORC1 complex (see 601231). Whole genome sequencing of DNA derived from the primary tumor and blood identified a 2-bp deletion in the TSC1 (605284) gene resulting in a frameshift truncation, and a nonsense mutation in the NF2 (607379) gene. Iyer et al. (2012) sequenced both genes in a second cohort of 96 high-grade bladder cancers and identified 5 additional somatic TSC1 mutations, whereas no additional NF2 mutations were detected. Subsequently, Iyer et al. (2012) explored whether TSC1 mutation is a biomarker of clinical benefit from everolimus therapy in bladder cancer, and studied 13 additional bladder cancer patients treated with everolimus. Three additional tumors harbored nonsense mutations in TSC1, including 2 patients who had minor responses to everolimus (17% and 24% tumor regression, respectively). Tumors from 8 of the 9 patients who showed disease progression were TSC1 wildtype. Patients with TSC1-mutant tumors remained on everolimus longer than those with wildtype tumors (7.7 vs 2.0 months, p = 0.004) with a significant improvement in time to recurrence (4.1 vs 1.8 months; hazard ratio = 18.5, 95% confidence interval 2.1 to 162, p = 0.001). Iyer et al. (2012) concluded that mTORC1-directed therapies may be most effective in cancer patients whose tumors harbor TSC1 somatic mutations. </p><p>Powles et al. (2014) examined the anti-PDL1 (605402) antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of urothelial bladder cancer (UBC). MPDL3280A is a high-affinity engineered human anti-PDL1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PDL1 with PD1 (PDCD1; 600244) and B7.1 (CD80; 112203). Because PDL1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PDL1. Powles et al. (2014) found that treatment with MPDL3280A resulted in rapid responses in metastatic UBC, with many occurring at the time of the first response assessment (6 weeks). Nearly all responses were ongoing at the data cutoff. In a phase I expansion study, Powles et al. (2014) showed that tumors expressing PDL1-positive tumor-infiltrating immune cells had particularly high response rates. MPDL3280A has a favorable toxicity profile, including a lack of renal toxicity, which suggested that it might be better tolerated by patients with UBC than chemotherapy. Patients with UBC tend to be older and to have a higher incidence of renal impairment. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Krontiris and Cooper (1981); Leklem and Brown (1976); Lynch et al.
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(1979); Mahboubi et al. (1981)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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Powles, T., Eder, J. P., Fine, G. D., Braiteh, F. S., Loriot, Y., Cruz, C., Bellmunt, J., Burris, H. A., Petrylak, D. P., Teng, S., Shen, X., Boyd, Z., Hegde, P. S., Chen, D. S., Vogelzang, N. J.
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<strong>MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.</strong>
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