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Entry
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- #613347 - PANCREATIC CANCER, SUSCEPTIBILITY TO, 2
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- OMIM
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<p>
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<span class="h4">#613347</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#clinicalManagement">Clinical Management</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=PANCREATIC CANCER" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3708&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1247/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/9069" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=613347[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1333" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 1333<br />
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">ICD+</a>
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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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613347
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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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PANCREATIC CANCER, SUSCEPTIBILITY TO, 2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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PNCA2
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<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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</thead>
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<tbody>
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<td>
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<span class="mim-font">
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<a href="/geneMap/13/83?start=-3&limit=10&highlight=83">
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13q13.1
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Pancreatic cancer 2}
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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/613347"> 613347 </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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</td>
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<td>
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<span class="mim-font">
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BRCA2
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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/600185"> 600185 </a>
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</span>
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</td>
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</tbody>
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</table>
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<div class="btn-group">
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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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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/613347" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/613347" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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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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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because susceptibility to pancreatic cancer is conferred by heterozygous mutation in the BRCA2 gene (<a href="/entry/600185">600185</a>) on chromosome 13q13.</p><p>For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic carcinoma, see <a href="/entry/260350">260350</a>.</p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="mapping" class="mim-anchor"></a>
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<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<div id="mimMappingFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#6" class="mim-tip-reference" title="Schutte, M., da Costa, L. T., Hahn, S. A., Moskaluk, C., Hoque, A. T. M. S., Rozenblum, E., Weinstein, C. L., Bittner, M., Meltzer, P. S., Trent, J. M., Yeo, C. J., Hruban, R. H., Kern, S. E. <strong>Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region.</strong> Proc. Nat. Acad. Sci. 92: 5950-5954, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7597059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7597059</a>] [<a href="https://doi.org/10.1073/pnas.92.13.5950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7597059">Schutte et al. (1995)</a> observed that, although pancreatic adenocarcinoma is relatively frequent, description of the genetic alterations has been hampered for several reasons. Because of the aggressive clinical course, the number of resected specimens, especially at early stages of the cancer, have been somewhat limited. Furthermore, pancreatic adenocarcinomas characteristically exhibit an exuberant host desmoplastic response, resulting in a high mixture of nonneoplastic cells and hampering the molecular genetic analysis of primary tumor samples. Finally, familial patterns of pancreatic adenocarcinoma usually do not involve young ages of onset, high penetrance, or extensive pedigrees. <a href="#6" class="mim-tip-reference" title="Schutte, M., da Costa, L. T., Hahn, S. A., Moskaluk, C., Hoque, A. T. M. S., Rozenblum, E., Weinstein, C. L., Bittner, M., Meltzer, P. S., Trent, J. M., Yeo, C. J., Hruban, R. H., Kern, S. E. <strong>Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region.</strong> Proc. Nat. Acad. Sci. 92: 5950-5954, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7597059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7597059</a>] [<a href="https://doi.org/10.1073/pnas.92.13.5950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7597059">Schutte et al. (1995)</a> used the method of representational difference analysis (RDA), as described by <a href="#2" class="mim-tip-reference" title="Lisitsyn, N. A., Lisitsina, N. M., Dalbagni, G., Barker, P., Sanchez, C. A., Gnarra, J., Linehan, W. M., Reid, B. J., Wigler, M. H. <strong>Comparative genomic analysis of tumors: detection of DNA losses and amplification.</strong> Proc. Nat. Acad. Sci. 92: 151-155, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7816807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7816807</a>] [<a href="https://doi.org/10.1073/pnas.92.1.151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7816807">Lisitsyn et al. (1995)</a>, to demonstrate a homozygous deletion mapping to a 1-cM region at 13q12.3. The deletion was flanked by the markers D13S171 and D13S260 and lay within the 6-cM region identified as containing the BRCA2 locus of heritable breast cancer susceptibility. This suggests that the same gene may be involved in multiple tumor types and that its function is that of a tumor suppressor rather than that of a dominant oncogene. RDA is a means for isolating DNA fragments that are present in only 1 of 2 nearly identical complex genomes. It utilizes a subtractive hybridization method but differs from conventional methods by using 'representations' of the genomes that have a reduction in complexity. Representations are generated by a PCR-based size selection applied to the restriction fragments of both genomes. Moreover, RDA takes advantage of both subtractive hybridization and DNA reassociation kinetics to favor the reiterated PCR amplification of the difference between the 2 genomes. RDA can enrich difference products over a million-fold after 3 rounds of selection. The patient in whose pancreatic cancer the homozygous deletion was demonstrated was an 84-year-old woman who had successful resection of a right-sided colon carcinoma at the age of 61. Her mother had had an adenocarcinoma of the colon resected and died of breast carcinoma at age 80. Her mother's sister died of breast carcinoma at age 94. Her mother's brother died of 'stomach' cancer in his 80s. The patient's brother died of colorectal cancer at the age of 52. Whether the members of this kindred were hemizygous for the deletion in the 13q12.3 region was not determined; <a href="#6" class="mim-tip-reference" title="Schutte, M., da Costa, L. T., Hahn, S. A., Moskaluk, C., Hoque, A. T. M. S., Rozenblum, E., Weinstein, C. L., Bittner, M., Meltzer, P. S., Trent, J. M., Yeo, C. J., Hruban, R. H., Kern, S. E. <strong>Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region.</strong> Proc. Nat. Acad. Sci. 92: 5950-5954, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7597059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7597059</a>] [<a href="https://doi.org/10.1073/pnas.92.13.5950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7597059">Schutte et al. (1995)</a> stated that 'it will be of interest to determine whether the individuals of the presently reported familial cluster are hemizygous in (this) region.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7597059+7816807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#5" class="mim-tip-reference" title="Ozcelik, H., Schmocker, B., Di Nicola, N., Shi, X.-H., Langer, B., Moore, M., Taylor, B. R., Narod, S. A., Darlington, G., Andrulis, I. L., Gallinger, S., Redston, M. <strong>Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. (Letter)</strong> Nature Genet. 16: 17-18, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9140390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9140390</a>] [<a href="https://doi.org/10.1038/ng0597-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9140390">Ozcelik et al. (1997)</a> investigated the contribution of germline BRCA2 mutations to the development of pancreatic cancer in 41 patients seen over a 4-month period, and selected without regard for family history. Mutations were identified in 2 patients (4.9%); one had a previously undescribed 6076delGTTA mutation, and the other had a 6174delT mutation (<a href="/entry/600185#0009">600185.0009</a>). The latter patient was 1 of 13 Jewish individuals in the cohort. In a subsequent study of 26 pancreatic cancers in Jewish individuals seen over a 15-year period, they found the 6174delT mutation in 3; no 6174delT mutations were identified in 55 non-Jewish pancreatic controls. The investigators suggested that the ability to identify a population at high risk for the development of pancreatic cancer might provide an opportunity to develop and evaluate prevention and early detection protocols aimed at reducing mortality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9140390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate the role of germline mutations in the etiology of pancreatic cancer, <a href="#4" class="mim-tip-reference" title="Murphy, K. M., Brune, K. A., Griffin, C., Sollenberger, J. E., Petersen, G. M., Bansal, R., Hruban, R. H., Kern, S. E. <strong>Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%.</strong> Cancer Res. 62: 3789-3793, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12097290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12097290</a>]" pmid="12097290">Murphy et al. (2002)</a> analyzed samples from patients from kindreds in which 3 or more family members were affected with the disease, at least 2 of which were first-degree relatives. By direct sequencing of constitutional DNA, they analyzed 4 tumor suppressor candidate genes: MAP2K4 (<a href="/entry/601335">601335</a>), MADH4 (<a href="/entry/600993">600993</a>), ACVR1B (<a href="/entry/601300">601300</a>), and BRCA2. These genes are mutated in clinically sporadic pancreatic cancer, but germline mutations had either not been reported or were anecdotal in familial pancreatic cancer. In the first 3 of the 4 genes, no germline mutations were found, suggesting that they are unlikely to account for a significant number of inherited pancreatic cancers. On the other hand, BRCA2 gene sequencing revealed that 5 patients from the 29 kindreds tested (17.2%) had mutations that had previously been reported to be deleterious; a point mutation (met192 to thr) of unknown significance was also identified. Three patients harbored the common 6174delT frameshift mutation (<a href="/entry/600185#0009">600185.0009</a>), 1 had the splice site mutation IVS16-2A-G, and 1 had a novel splice site mutation IVS15-1G-A. A family history of breast cancer was reported in 2 of the 5 BRCA2 mutation carriers; none reported a family history of ovarian cancer. These findings confirmed an increased risk of pancreatic cancer in individuals with BRCA2 mutations and identified germline BRCA2 mutations as the most common inherited genetic alteration in familial pancreatic cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12097290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Zhen, D. B., Rabe, K. G., Gallinger, S., Syngal, S., Schwartz, A. G., Goggins, M. G., Hruban, R. H., Cote, M. L., McWilliams, R. R., Roberts, N. J., Cannon-Albright, L. A., Li, D., Moyes, K., Wenstrup, R. J., Hartman, A.-R., Seminara, D., Klein, A. P., Petersen, G. M. <strong>BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.</strong> Genet. Med. 17: 569-577, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25356972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25356972</a>] [<a href="https://doi.org/10.1038/gim.2014.153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25356972">Zhen et al. (2015)</a> tested germline DNA from 727 unrelated probands with pancreatic cancer and a positive family history for mutations in BRCA1 (<a href="/entry/113705">113705</a>) and BRCA2 (including deletions and rearrangements), PALB2 (<a href="/entry/610355">610355</a>), and CDKN2A (<a href="/entry/600160">600160</a>). Among these probands, 521 met criteria for familial pancreatic cancer (FPC; at least 2 affected first-degree relatives). The prevalence of deleterious mutations, excluding variants of unknown significance, among FPC probands was BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. FPC probands carried more mutations in the 4 genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%; OR = 2.40, 95% CI 1.06-5.44, p = 0.03). The probability of testing positive for deleterious mutations in any of the 4 genes ranged up to 10.4%, depending on family history of cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25356972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J.-O., Hochhauser, D., Arnold, D., Oh, D.-Y., Reinacher-Schick, A., Tortora, G., Algul, H., O'Reilly, E. M., McGuinness, D., Cui, K. Y., Schlienger, K., Locker, G. Y., Kindler, H. L. <strong>Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.</strong> New Eng. J. Med. 381: 317-327, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31157963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31157963</a>] [<a href="https://doi.org/10.1056/NEJMoa1903387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31157963">Golan et al. (2019)</a> conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib, a PARP (see <a href="/entry/173870">173870</a>) inhibitor, as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. The primary end point was progression-free survival, which was assessed by blinded independent central review. Of the 3,315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 received olaparib and 62 received placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval (CI), 0.35 to 0.82; p = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups. There was no significant between-group difference in health-related quality of life. The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group. <a href="#1" class="mim-tip-reference" title="Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J.-O., Hochhauser, D., Arnold, D., Oh, D.-Y., Reinacher-Schick, A., Tortora, G., Algul, H., O'Reilly, E. M., McGuinness, D., Cui, K. Y., Schlienger, K., Locker, G. Y., Kindler, H. L. <strong>Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.</strong> New Eng. J. Med. 381: 317-327, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31157963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31157963</a>] [<a href="https://doi.org/10.1056/NEJMoa1903387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31157963">Golan et al. (2019)</a> concluded that among patients with germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31157963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Genetic studies of familial pancreatic cancer have led to the identification of mutations in the BRCA2 gene in approximately 12 to 20% of families, often in the absence of cases of breast or ovarian carcinoma (<a href="#3" class="mim-tip-reference" title="McWilliams, R. R., Rabe, K. G., Olswold, C., De Andrade, M., Petersen, G. M. <strong>Risk of malignancy in first-degree relatives of patients with pancreatic carcinoma.</strong> Cancer 104: 388-394, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15912495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15912495</a>] [<a href="https://doi.org/10.1002/cncr.21166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15912495">McWilliams et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15912495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J.-O., Hochhauser, D., Arnold, D., Oh, D.-Y., Reinacher-Schick, A., Tortora, G., Algul, H., O'Reilly, E. M., McGuinness, D., Cui, K. Y., Schlienger, K., Locker, G. Y., Kindler, H. L.
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New Eng. J. Med. 381: 317-327, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31157963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31157963</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31157963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1903387" target="_blank">Full Text</a>]
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<strong>Comparative genomic analysis of tumors: detection of DNA losses and amplification.</strong>
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Proc. Nat. Acad. Sci. 92: 151-155, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7816807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7816807</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7816807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Cancer 104: 388-394, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15912495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15912495</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15912495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Murphy2002" class="mim-anchor"></a>
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<div class="">
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Murphy, K. M., Brune, K. A., Griffin, C., Sollenberger, J. E., Petersen, G. M., Bansal, R., Hruban, R. H., Kern, S. E.
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<strong>Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%.</strong>
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Cancer Res. 62: 3789-3793, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12097290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12097290</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12097290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="5" class="mim-anchor"></a>
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<a id="Ozcelik1997" class="mim-anchor"></a>
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<p class="mim-text-font">
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Ozcelik, H., Schmocker, B., Di Nicola, N., Shi, X.-H., Langer, B., Moore, M., Taylor, B. R., Narod, S. A., Darlington, G., Andrulis, I. L., Gallinger, S., Redston, M.
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<strong>Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. (Letter)</strong>
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Nature Genet. 16: 17-18, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9140390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9140390</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9140390" 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/ng0597-17" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
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<a id="Schutte1995" class="mim-anchor"></a>
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<p class="mim-text-font">
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Schutte, M., da Costa, L. T., Hahn, S. A., Moskaluk, C., Hoque, A. T. M. S., Rozenblum, E., Weinstein, C. L., Bittner, M., Meltzer, P. S., Trent, J. M., Yeo, C. J., Hruban, R. H., Kern, S. E.
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<strong>Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region.</strong>
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Proc. Nat. Acad. Sci. 92: 5950-5954, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7597059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7597059</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7597059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.92.13.5950" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Zhen2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhen, D. B., Rabe, K. G., Gallinger, S., Syngal, S., Schwartz, A. G., Goggins, M. G., Hruban, R. H., Cote, M. L., McWilliams, R. R., Roberts, N. J., Cannon-Albright, L. A., Li, D., Moyes, K., Wenstrup, R. J., Hartman, A.-R., Seminara, D., Klein, A. P., Petersen, G. M.
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<strong>BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.</strong>
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Genet. Med. 17: 569-577, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25356972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25356972</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25356972" 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/gim.2014.153" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/12/2019
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Ada Hamosh - updated : 10/19/2015
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Creation Date:
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<span class="mim-text-font">
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Anne M. Stumpf : 4/8/2010
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alopez : 08/12/2019
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carol : 05/27/2016<br>alopez : 10/19/2015<br>terry : 11/30/2010<br>alopez : 4/9/2010<br>alopez : 4/8/2010
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<span class="mim-font">
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<strong>#</strong> 613347
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PANCREATIC CANCER, SUSCEPTIBILITY TO, 2
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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PNCA2
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<strong>ORPHA:</strong> 1333;
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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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13q13.1
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<span class="mim-font">
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{Pancreatic cancer 2}
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<span class="mim-font">
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613347
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<span class="mim-font">
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<span class="mim-font">
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3
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<span class="mim-font">
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BRCA2
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<span class="mim-font">
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600185
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because susceptibility to pancreatic cancer is conferred by heterozygous mutation in the BRCA2 gene (600185) on chromosome 13q13.</p><p>For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic carcinoma, see 260350.</p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Schutte et al. (1995) observed that, although pancreatic adenocarcinoma is relatively frequent, description of the genetic alterations has been hampered for several reasons. Because of the aggressive clinical course, the number of resected specimens, especially at early stages of the cancer, have been somewhat limited. Furthermore, pancreatic adenocarcinomas characteristically exhibit an exuberant host desmoplastic response, resulting in a high mixture of nonneoplastic cells and hampering the molecular genetic analysis of primary tumor samples. Finally, familial patterns of pancreatic adenocarcinoma usually do not involve young ages of onset, high penetrance, or extensive pedigrees. Schutte et al. (1995) used the method of representational difference analysis (RDA), as described by Lisitsyn et al. (1995), to demonstrate a homozygous deletion mapping to a 1-cM region at 13q12.3. The deletion was flanked by the markers D13S171 and D13S260 and lay within the 6-cM region identified as containing the BRCA2 locus of heritable breast cancer susceptibility. This suggests that the same gene may be involved in multiple tumor types and that its function is that of a tumor suppressor rather than that of a dominant oncogene. RDA is a means for isolating DNA fragments that are present in only 1 of 2 nearly identical complex genomes. It utilizes a subtractive hybridization method but differs from conventional methods by using 'representations' of the genomes that have a reduction in complexity. Representations are generated by a PCR-based size selection applied to the restriction fragments of both genomes. Moreover, RDA takes advantage of both subtractive hybridization and DNA reassociation kinetics to favor the reiterated PCR amplification of the difference between the 2 genomes. RDA can enrich difference products over a million-fold after 3 rounds of selection. The patient in whose pancreatic cancer the homozygous deletion was demonstrated was an 84-year-old woman who had successful resection of a right-sided colon carcinoma at the age of 61. Her mother had had an adenocarcinoma of the colon resected and died of breast carcinoma at age 80. Her mother's sister died of breast carcinoma at age 94. Her mother's brother died of 'stomach' cancer in his 80s. The patient's brother died of colorectal cancer at the age of 52. Whether the members of this kindred were hemizygous for the deletion in the 13q12.3 region was not determined; Schutte et al. (1995) stated that 'it will be of interest to determine whether the individuals of the presently reported familial cluster are hemizygous in (this) region.' </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>Ozcelik et al. (1997) investigated the contribution of germline BRCA2 mutations to the development of pancreatic cancer in 41 patients seen over a 4-month period, and selected without regard for family history. Mutations were identified in 2 patients (4.9%); one had a previously undescribed 6076delGTTA mutation, and the other had a 6174delT mutation (600185.0009). The latter patient was 1 of 13 Jewish individuals in the cohort. In a subsequent study of 26 pancreatic cancers in Jewish individuals seen over a 15-year period, they found the 6174delT mutation in 3; no 6174delT mutations were identified in 55 non-Jewish pancreatic controls. The investigators suggested that the ability to identify a population at high risk for the development of pancreatic cancer might provide an opportunity to develop and evaluate prevention and early detection protocols aimed at reducing mortality. </p><p>To investigate the role of germline mutations in the etiology of pancreatic cancer, Murphy et al. (2002) analyzed samples from patients from kindreds in which 3 or more family members were affected with the disease, at least 2 of which were first-degree relatives. By direct sequencing of constitutional DNA, they analyzed 4 tumor suppressor candidate genes: MAP2K4 (601335), MADH4 (600993), ACVR1B (601300), and BRCA2. These genes are mutated in clinically sporadic pancreatic cancer, but germline mutations had either not been reported or were anecdotal in familial pancreatic cancer. In the first 3 of the 4 genes, no germline mutations were found, suggesting that they are unlikely to account for a significant number of inherited pancreatic cancers. On the other hand, BRCA2 gene sequencing revealed that 5 patients from the 29 kindreds tested (17.2%) had mutations that had previously been reported to be deleterious; a point mutation (met192 to thr) of unknown significance was also identified. Three patients harbored the common 6174delT frameshift mutation (600185.0009), 1 had the splice site mutation IVS16-2A-G, and 1 had a novel splice site mutation IVS15-1G-A. A family history of breast cancer was reported in 2 of the 5 BRCA2 mutation carriers; none reported a family history of ovarian cancer. These findings confirmed an increased risk of pancreatic cancer in individuals with BRCA2 mutations and identified germline BRCA2 mutations as the most common inherited genetic alteration in familial pancreatic cancer. </p><p>Zhen et al. (2015) tested germline DNA from 727 unrelated probands with pancreatic cancer and a positive family history for mutations in BRCA1 (113705) and BRCA2 (including deletions and rearrangements), PALB2 (610355), and CDKN2A (600160). Among these probands, 521 met criteria for familial pancreatic cancer (FPC; at least 2 affected first-degree relatives). The prevalence of deleterious mutations, excluding variants of unknown significance, among FPC probands was BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. FPC probands carried more mutations in the 4 genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%; OR = 2.40, 95% CI 1.06-5.44, p = 0.03). The probability of testing positive for deleterious mutations in any of the 4 genes ranged up to 10.4%, depending on family history of cancers. </p>
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<h4>
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<strong>Clinical Management</strong>
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<span class="mim-text-font">
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<p>Golan et al. (2019) conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib, a PARP (see 173870) inhibitor, as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. The primary end point was progression-free survival, which was assessed by blinded independent central review. Of the 3,315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 received olaparib and 62 received placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval (CI), 0.35 to 0.82; p = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups. There was no significant between-group difference in health-related quality of life. The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group. Golan et al. (2019) concluded that among patients with germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</div>
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<span class="mim-text-font">
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<p>Genetic studies of familial pancreatic cancer have led to the identification of mutations in the BRCA2 gene in approximately 12 to 20% of families, often in the absence of cases of breast or ovarian carcinoma (McWilliams et al., 2005). </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Lisitsyn, N. A., Lisitsina, N. M., Dalbagni, G., Barker, P., Sanchez, C. A., Gnarra, J., Linehan, W. M., Reid, B. J., Wigler, M. H.
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McWilliams, R. R., Rabe, K. G., Olswold, C., De Andrade, M., Petersen, G. M.
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Murphy, K. M., Brune, K. A., Griffin, C., Sollenberger, J. E., Petersen, G. M., Bansal, R., Hruban, R. H., Kern, S. E.
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Zhen, D. B., Rabe, K. G., Gallinger, S., Syngal, S., Schwartz, A. G., Goggins, M. G., Hruban, R. H., Cote, M. L., McWilliams, R. R., Roberts, N. J., Cannon-Albright, L. A., Li, D., Moyes, K., Wenstrup, R. J., Hartman, A.-R., Seminara, D., Klein, A. P., Petersen, G. M.
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Ada Hamosh - updated : 08/12/2019<br>Ada Hamosh - updated : 10/19/2015
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Anne M. Stumpf : 4/8/2010
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alopez : 08/12/2019<br>carol : 05/27/2016<br>alopez : 10/19/2015<br>terry : 11/30/2010<br>alopez : 4/9/2010<br>alopez : 4/8/2010
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