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<title>
Entry
- #167000 - OVARIAN CANCER
- OMIM
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<span class="h4">#167000</span>
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<strong>Table of Contents</strong>
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<li role="presentation">
<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
<a href="/clinicalSynopsis/167000"><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">
<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
</li>
<li role="presentation" style="margin-left: 1em">
<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#clinicalManagement">Clinical Management</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
<a href="#references"><strong>References</strong></a>
</li>
<li role="presentation">
<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=(OVARIAN CANCER) OR (ERBB2 OR CDH1 OR OPCML OR AKT1 OR PIK3CA OR CTNNB1 OR PRKN)" 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.ncbi.nlm.nih.gov/gtr/all/tests/?term=167000[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 style="display: table-cell;">Animal Models</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:2394" 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>
<div><a href="http://www.informatics.jax.org/disease/167000" 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>
<div><a href="https://wormbase.org/resources/disease/DOID:2394" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
<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 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">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 363443007<br />
<strong>ICD10CM:</strong> C56<br />
<strong>ICD9CM:</strong> 183.0<br />
<strong>DO:</strong> 2394<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
167000
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
OVARIAN CANCER
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
OVARIAN CANCER, EPITHELIAL, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/198?start=-3&limit=10&highlight=198">
3p22.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/167000"> 167000 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
CTNNB1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/116806"> 116806 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/876?start=-3&limit=10&highlight=876">
3q26.32
</a>
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/167000"> 167000 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
PIK3CA
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/171834"> 171834 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/1011?start=-3&limit=10&highlight=1011">
6q26
</a>
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/167000"> 167000 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
PRKN
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602544"> 602544 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/1098?start=-3&limit=10&highlight=1098">
11q25
</a>
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/167000"> 167000 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
OPCML
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600632"> 600632 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/593?start=-3&limit=10&highlight=593">
14q32.33
</a>
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/167000"> 167000 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
AKT1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164730"> 164730 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/582?start=-3&limit=10&highlight=582">
16q22.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/167000"> 167000 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
CDH1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/192090"> 192090 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/491?start=-3&limit=10&highlight=491">
17q12
</a>
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/167000"> 167000 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
ERBB2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164870"> 164870 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
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<li><a href="/graph/linear/167000" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </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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<div class="small" style="margin: 5px">
<div>
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<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- 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 />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Ovarian cancer <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/363443007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">363443007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/123843001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">123843001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C56" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C56</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/183.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">183.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1140680&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1140680</a>, <a href="https://bioportal.bioontology.org/search?q=C0919267&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0919267</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100615" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100615</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100615" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100615</a>]</span><br /> -
Dysgerminoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60718004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60718004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013377&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013377</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100621" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100621</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100621" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100621</a>]</span><br /> -
Ovarian papillary adenocarcinoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4024979&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4024979</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006774" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006774</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006774" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006774</a>]</span><br /> -
Serous ovarian cystadenocarcinoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0279663&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0279663</a>]</span><br /> -
Breast cancer <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254838004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254838004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254837009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254837009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C50-C50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C50-C50</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/C50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0678222&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0678222</a>, <a href="https://bioportal.bioontology.org/search?q=C0006142&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0006142</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003002</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003002</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Frequent loss of heterozygosity at 6q24-q27 <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194093&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194093</a>]</span><br />
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because ovarian cancer has been associated with somatic changes in several genes, including OPCML (<a href="/entry/600632">600632</a>), PIK3CA (<a href="/entry/171834">171834</a>), AKT1 (<a href="/entry/164730">164730</a>), CTNNB1 (<a href="/entry/116806">116806</a>), RRAS2 (<a href="/entry/600098">600098</a>), CDH1 (<a href="/entry/192090">192090</a>), ERBB2 (<a href="/entry/164870">164870</a>), and PARK2 (<a href="/entry/602544">602544</a>).</p><p>See also <a href="/entry/607893">607893</a> for an ovarian cancer susceptibility locus (OVCAS1) that has been mapped to chromosome 3p25-p22.</p><p>Familial ovarian cancer may be part of other cancer syndromes. See susceptibility to familial breast-ovarian cancer 1 and 2 (<a href="/entry/604370">604370</a> and <a href="/entry/612555">612555</a>), due to mutations in the BRCA1 (<a href="/entry/113705">113705</a>) and BRCA2 (<a href="/entry/600185">600185</a>) genes, respectively; and Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (see, e.g., HNPCC1; <a href="/entry/120435">120435</a>), due to mutations in DNA mismatch repair genes such as MSH2 (<a href="/entry/609309">609309</a>), MSH3 (<a href="/entry/600887">600887</a>), MSH6 (<a href="/entry/600678">600678</a>), and MLH1 (<a href="/entry/120436">120436</a>).</p>
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<strong>Description</strong>
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<p>Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (<a href="#6" class="mim-tip-reference" title="Chi, D. S., Liao, J. B., Leon, L. F., Venkatraman, E. S., Hensley, M. L., Bhaskaran, D., Hoskins, W. J. &lt;strong&gt;Identification of prognostic factors in advanced epithelial ovarian carcinoma.&lt;/strong&gt; Gynec. Oncol. 82: 532-537, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11520151/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11520151&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/gyno.2001.6328&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11520151">Chi et al., 2001</a>). These typical features relate to the biology of the disease, which is a principal determinant of outcome (<a href="#1" class="mim-tip-reference" title="Auersperg, N., Wong, A. S. T., Choi, K.-C., Kang, S. K., Leung, P. C. K. &lt;strong&gt;Ovarian surface epithelium: biology, endocrinology, and pathology.&lt;/strong&gt; Endocr. Rev. 22: 255-288, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11294827/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11294827&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/edrv.22.2.0422&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11294827">Auersperg et al., 2001</a>). Epithelial ovarian cancer is the most common form and encompasses 5 major histologic subtypes: papillary serous, endometrioid, mucinous, clear cell, and transitional cell. Epithelial ovarian cancer arises as a result of genetic alterations sustained by the ovarian surface epithelium (<a href="#46" class="mim-tip-reference" title="Stany, M. P., Bonome, T., Wamunyokoli, F., Zorn, K., Ozbun, L., Park, D.-C., Hao, K., Boyd, J., Sood, A. K., Gershenson, D. M., Berkowitz, R. S., Mok, S. C., Birrer, M. J. &lt;strong&gt;Classification of ovarian cancer: a genomic analysis.&lt;/strong&gt; Adv. Exp. Med. Biol. 622: 23-33, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18546616/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18546616&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18546616[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/978-0-387-68969-2_3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18546616">Stany et al., 2008</a>; <a href="#45" class="mim-tip-reference" title="Soslow, R. A. &lt;strong&gt;Histologic subtypes of ovarian carcinoma: an overview.&lt;/strong&gt; Int. J. Gynec. Path. 27: 161-174, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18317227/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18317227&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/PGP.0b013e31815ea812&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18317227">Soslow, 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18546616+18317227+11294827+11520151" 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>There are several early reports of familial ovarian cancer showing autosomal dominant inheritance. Some of these families may have had the breast-ovarian cancer syndrome or Lynch syndrome. <a href="#27" class="mim-tip-reference" title="Liber, A. F. &lt;strong&gt;Ovarian cancer in mother and five daughters.&lt;/strong&gt; Arch. Path. 49: 280-290, 1950.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15406261/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15406261&lt;/a&gt;]" pmid="15406261">Liber (1950)</a> described a family with histologically proven papillary adenocarcinoma of the ovary in 5 sisters and their mother. <a href="#20" class="mim-tip-reference" title="Jackson, S. M. &lt;strong&gt;Ovarian dysgerminoma in three generations?&lt;/strong&gt; J. Med. Genet. 4: 112-113, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5619989/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5619989&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.4.2.112&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5619989">Jackson (1967)</a> reported a Jamaican family in which grandmother, mother, and daughter developed ovarian tumors; 2 tumors were known to have been dysgerminomas (see <a href="/entry/603737">603737</a>). <a href="#25" class="mim-tip-reference" title="Lewis, A. C. W., Davison, B. C. C. &lt;strong&gt;Familial ovarian cancer.&lt;/strong&gt; Lancet 294: 235-237, 1969. Note: Originally Volume II.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4184107/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4184107&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(69)90004-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4184107">Lewis and Davison (1969)</a> described a family in which 5 of 6 sisters and their mother had ovarian cancer. One of the 5 had a malignant ovarian cyst but subsequently died of colon cancer. Prophylactic oophorectomy was performed in the sixth sister and in 5 females of the following generation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15406261+4184107+5619989" 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="Li, F. P., Rapoport, A. H., Fraumeni, J. F., Jr., Jensen, R. D. &lt;strong&gt;Familial ovarian carcinoma.&lt;/strong&gt; JAMA 214: 1559-1561, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4320145/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4320145&lt;/a&gt;]" pmid="4320145">Li et al. (1970)</a> reported a family in which 7 women, including 4 sisters, had ovarian carcinoma. Ovarian cancer was suspected in 3 other women of the family. <a href="#34" class="mim-tip-reference" title="Philipp, E. E. &lt;strong&gt;Familial carcinoma of the ovary: case report.&lt;/strong&gt; Brit. J. Obstet. Gynaec. 86: 152-153, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/427055/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;427055&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1471-0528.1979.tb10584.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="427055">Philipp (1979)</a> described a family with multiple cases of poorly differentiated cystadenocarcinoma of the ovary. The 4 relatives with ovarian carcinoma were the proband's mother, maternal aunt, that woman's daughter, and the daughter of another maternal aunt. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4320145+427055" 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="#48" class="mim-tip-reference" title="Whang-Peng, J., Knutsen, T., Douglass, E. C., Chu, E., Ozols, R. F., Hogan, W. M., Young, R. C. &lt;strong&gt;Cytogenetic studies in ovarian cancer.&lt;/strong&gt; Cancer Genet. Cytogenet. 11: 91-106, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6690026/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6690026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0165-4608(84)90102-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6690026">Whang-Peng et al. (1984)</a> performed cytogenetic studies on ovarian tumor tissue from 44 patients with various forms of epithelial ovarian cancer. All 44 samples had numerical abnormalities, and 39 had structural abnormalities involving multiple chromosomes. Clone formation and the number of chromosomes involved in structural abnormalities increased with duration of disease and were more extensive in patients treated with chemotherapy compared to patients treated with surgery alone. Aneuploidy was observed in all patients and there was considerable variation in the chromosome numbers, often ranging from diploidy to triploidy to tetraploidy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6690026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Chromosome 2q22.1</em></strong></p><p>
Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, <a href="#44" class="mim-tip-reference" title="Song, H., Ramus, S. J., Kjaer, S. K., DiCioccio, R. A., Chenevix-Trench, G., Pearce, C. L., Hogdall, E., Whittemore, A. S., McGuire, V., Hogdall, C., Blaakaer, J., Wu, A. H., and 39 others. &lt;strong&gt;Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study.&lt;/strong&gt; Hum. Molec. Genet. 18: 2297-2304, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19304784/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19304784&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp138&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19304784">Song et al. (2009)</a> evaluated 11 of the most significant loci from a previously reported breast cancer genomewide association study for association with invasive ovarian cancer (<a href="#12" class="mim-tip-reference" title="Easton, D. F., Pooley, K. A., Dunning, A. M., Pharoah, P. D. P., Thompson, D., Ballinger, D. G., Struewing, J. P., Morrison, J., Field, H., Luben, R., Wareham, N., Ahmed, S., and 93 others. &lt;strong&gt;Genome-wide association study identifies novel breast cancer susceptibility loci.&lt;/strong&gt; Nature 447: 1087-1093, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17529967/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17529967&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17529967[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature05887&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17529967">Easton et al., 2007</a>). The 11 SNPs were initially genotyped in 2,927 invasive ovarian cancer cases and 4,143 controls from 6 ovarian cancer case-control studies. Only <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4954956;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4954956</a> located less than 7.0 kb upstream of the NXPH2 gene (<a href="/entry/604635">604635</a>) was significantly associated with ovarian cancer risk both in the replication study and in combined analysis of 5,353 patients and 8,453 controls. This association was stronger for the serous histologic subtype (p = 0.0004; OR, 1.14) than for all types of ovarian cancer (p = 0.05; OR, 1.07). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19304784+17529967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Chromosome 6q25</em></strong></p><p>
<a href="#40" class="mim-tip-reference" title="Saito, S., Saito, H., Koi, S., Sagae, S., Kudo, R., Saito, J., Noda, K., Nakamura, Y. &lt;strong&gt;Fine-scale deletion mapping of the distal long arm of chromosome 6 in 70 human ovarian cancers.&lt;/strong&gt; Cancer Res. 52: 5815-5817, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1394208/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1394208&lt;/a&gt;]" pmid="1394208">Saito et al. (1992)</a> examined loss of heterozygosity (LOH) in 70 ovarian tumors using 9 RFLP markers located at chromosome 6q24-q27. Among 33 informative serous cancers, 17 (52%) showed allelic loss at a few or all loci examined, whereas only 1 of 15 mucinous-type tumors and 2 of 12 clear-cell tumors showed LOH. A detailed deletion map delineated a 1.9-cM region, within which the authors postulated the existence of a tumor suppressor gene involved in ovarian carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1394208" 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 54 fresh and paraffin-embedded invasive ovarian epithelial tumor tissues, <a href="#8" class="mim-tip-reference" title="Colitti, C. V., Rodabaugh, K. J., Welch, W. R., Berkowitz, R. S., Mok, S. C. &lt;strong&gt;A novel 4 cM minimal deletion unit on chromosome 6q25.1-q25.2 associated with high grade invasive epithelial ovarian carcinomas.&lt;/strong&gt; Oncogene 16: 555-559, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9484846/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9484846&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.onc.1201523&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9484846">Colitti et al. (1998)</a> used tandem repeat markers on chromosome 6q25 to delineate a 4-cM minimal region of LOH of 6q25.1-q25.2 between markers D6S473 and D6S448. Loss of heterozygosity was observed more frequently at the loci defined by marker D6S473 (14 of 32 informative cases, 44%) and marker D6S448 (17 of 40 informative cases, 43%). LOH at D6S473 correlated significantly both with serous compared to non-serous ovarian tumors (p = 0.040), and with high-grade compared to low-grade specimens (p = 0.023). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9484846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Chromosome 9p24</em></strong></p><p>
By transfection of NIH-3T3 cells with genomic DNA from a human ovarian adenocarcinoma tumor cell line, <a href="#19" class="mim-tip-reference" title="Halverson, D., Modi, W., Dean, M., Gelmann, E. P., Dunn, K. J., Clanton, D., Oskarsson, M., O&#x27;Brien, S. J., Blair, D. G. &lt;strong&gt;An oncogenic chromosome 8-9 gene fusion isolated following transfection of human ovarian carcinoma cell line DNA.&lt;/strong&gt; Oncogene 5: 1085-1089, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1973829/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1973829&lt;/a&gt;]" pmid="1973829">Halverson et al. (1990)</a> identified a rearranged human DNA sequence that was generated during transfection and induced both morphologic transformation and tumorigenesis. One fragment mapped to human chromosome 9p24 and the other to human chromosome 8. Because rat ovarian surface epithelial cells transformed spontaneously in vitro have been found to have homozygous deletions of the interferon alpha gene (IFNA; <a href="/entry/147660">147660</a>) on 9p22, suggesting inactivation of a tumor-suppressor gene in that region may be crucial for the development of ovarian cancer, <a href="#5" class="mim-tip-reference" title="Chenevix-Trench, G., Kerr, J., Friedlander, M., Hurst, T., Sanderson, B., Coglan, M., Ward, B., Leary, J., Khoo, S.-K. &lt;strong&gt;Homozygous deletions on the short arm of chromosome 9 in ovarian adenocarcinoma cell lines and loss of heterozygosity in sporadic tumors.&lt;/strong&gt; Am. J. Hum. Genet. 55: 143-149, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8023842/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8023842&lt;/a&gt;]" pmid="8023842">Chenevix-Trench et al. (1994)</a> used microsatellite markers and Southern analysis to examine the homologous region in humans, 9p, for deletions in sporadic ovarian adenocarcinomas and ovarian tumor cell lines. Loss of heterozygosity occurred in 34 (37%) of 91 informative sporadic tumors, including some benign, low-malignant-potential and early-stage tumors, suggesting that it is an early event in the development of ovarian adenocarcinoma. Furthermore, homozygous deletions on 9p were found in 2 of 10 independent cell lines. Deletion mapping of the tumors and cell lines indicated that the candidate suppressor gene inactivated as a consequence lies between D9S171 and the IFNA locus. This region is deleted in several other tumors and contains a melanoma predisposition locus (<a href="/entry/155601">155601</a>). In a note added in proof, <a href="#5" class="mim-tip-reference" title="Chenevix-Trench, G., Kerr, J., Friedlander, M., Hurst, T., Sanderson, B., Coglan, M., Ward, B., Leary, J., Khoo, S.-K. &lt;strong&gt;Homozygous deletions on the short arm of chromosome 9 in ovarian adenocarcinoma cell lines and loss of heterozygosity in sporadic tumors.&lt;/strong&gt; Am. J. Hum. Genet. 55: 143-149, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8023842/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8023842&lt;/a&gt;]" pmid="8023842">Chenevix-Trench et al. (1994)</a> suggested that the target of these 9p deletions might be CDKN2 (<a href="/entry/600160">600160</a>) as described by <a href="#22" class="mim-tip-reference" title="Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S. V., Stockert, E., Day, R. S., III, Johnson, B. E., Skolnick, M. H. &lt;strong&gt;A cell cycle regulator potentially involved in genesis of many tumor types.&lt;/strong&gt; Science 264: 436-440, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8153634/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8153634&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.8153634&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8153634">Kamb et al. (1994)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8153634+8023842+1973829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Chromosome 11q25</em></strong></p><p>
Loss of heterozygosity studies indicated that a tumor suppressor gene associated with sporadic ovarian cancer may reside at chromosome 11q25 (<a href="#16" class="mim-tip-reference" title="Gabra, H., Watson, J. E. V., Taylor, K. J., Mackay, J., Leonard, R. C. F., Steel, C. M., Porteous, D. J., Smyth, J. F. &lt;strong&gt;Definition and refinement of a region of loss of heterozygosity at 11q23.3-q24.3 in epithelial ovarian cancer associated with poor prognosis.&lt;/strong&gt; Cancer Res. 56: 950-954, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8640783/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8640783&lt;/a&gt;]" pmid="8640783">Gabra et al., 1996</a>; <a href="#24" class="mim-tip-reference" title="Launonen, V., Stenback, F., Puistola, U., Bloigu, R., Huusko, P., Kytola, S., Kauppila, A., Winqvist, R. &lt;strong&gt;Chromosome 11q23.3-q25 LOH in ovarian cancer: association with a more aggressive disease course and involved subregions.&lt;/strong&gt; Gynec. Oncol. 71: 299-304, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9826475/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9826475&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/gyno.1998.5186&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9826475">Launonen et al., 1998</a>). In tumor tissue from 118 individuals with epithelial ovarian cancer, <a href="#42" class="mim-tip-reference" title="Sellar, G. C., Watt, K. P., Rabiasz, G. J., Stronach, E. A., Li, L., Miller, E. P., Massie, C. E., Miller, J., Contreras-Moreira, B., Scott, D., Brown, I., Williams, A. R., Bates, P. A., Smyth, J. F., Gabra, H. &lt;strong&gt;OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer.&lt;/strong&gt; Nature Genet. 34: 337-343, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12819783/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12819783&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1183&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12819783">Sellar et al. (2003)</a> observed a peak LOH rate of 49% (36 of 74 informative cases) across 11q25 at D11S4085. Conversely, LOH analysis of 39 pairs of DNA from individuals with colorectal cancer (see <a href="/entry/114500">114500</a>) and normal DNA showed an LOH rate at D11S4085 of only 23% (6 of 26 informative cases), with no evidence of complete LOH. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12819783+8640783+9826475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Chromosome 17p</em></strong></p><p>
<a href="#13" class="mim-tip-reference" title="Eccles, D. M., Cranston, G., Steel, C. M., Nakamura, Y., Leonard, R. C. F. &lt;strong&gt;Allele losses on chromosome 17 in human epithelial ovarian carcinoma.&lt;/strong&gt; Oncogene 5: 1599-1601, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2250917/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2250917&lt;/a&gt;]" pmid="2250917">Eccles et al. (1990)</a> found LOH of chromosome 17p in 69% of 16 epithelial ovarian cancer tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2250917" 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="#41" class="mim-tip-reference" title="Schultz, D. C., Vanderveer, L., Berman, D. B., Hamilton, T. C., Wong, A. J., Godwin, A. K. &lt;strong&gt;Identification of two candidate tumor suppressor genes on chromosome 17p13.3.&lt;/strong&gt; Cancer Res. 56: 1997-2002, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8616839/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8616839&lt;/a&gt;]" pmid="8616839">Schultz et al. (1996)</a> identified 2 genes, OVCA1 (DPH1; <a href="/entry/603527">603527</a>) and OVCA2 (<a href="/entry/607896">607896</a>), within a minimum region of allelic loss on chromosome 17p13.3 in a cohort of ovarian tumors. Expression of OVCA1 and OVCA2 was reduced or undetectable in ovarian tumor tissue and cell lines compared with normal ovarian epithelial cells. The findings provided evidence for 1 or more possible tumor suppressor genes on chromosome 17p distinct from the TP53 gene (<a href="/entry/191170">191170</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8616839" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Phillips, N. J., Zeigler, M. R., Deaven, L. L. &lt;strong&gt;A cDNA from the ovarian cancer critical region of deletion on chromosome 17p13.3.&lt;/strong&gt; Cancer Lett. 102: 85-90, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8603384/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8603384&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0304-3835(96)04169-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8603384">Phillips et al. (1996)</a> also identified the DPH1 (OVCA1) gene within the region on chromosome 17p13.3 that is deleted in 80% of all ovarian epithelial malignancies. They suggested that it may act as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8603384" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Chromosome 17q</em></strong></p><p>
Chromosome 17q contains several genes implicated in ovarian cancer: the BRCA1 gene (<a href="/entry/113705">113705</a>) on 17q21, the ERBB2 gene (<a href="/entry/164870">164870</a>) on 17q21.1, and the SEPT9 gene (<a href="/entry/604061">604061</a>) on 17q25.</p><p><a href="#13" class="mim-tip-reference" title="Eccles, D. M., Cranston, G., Steel, C. M., Nakamura, Y., Leonard, R. C. F. &lt;strong&gt;Allele losses on chromosome 17 in human epithelial ovarian carcinoma.&lt;/strong&gt; Oncogene 5: 1599-1601, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2250917/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2250917&lt;/a&gt;]" pmid="2250917">Eccles et al. (1990)</a> found LOH of 17q in 77% of 16 epithelial ovarian cancer tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2250917" 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="#17" class="mim-tip-reference" title="Godwin, A. K., Vanderveer, L., Schultz, D. C., Lynch, H. T., Altomare, D. A., Buetow, K. H., Daly, M., Getts, L. A., Masny, A., Rosenblum, N., Hogan, M., Ozols, R. F., Hamilton, T. C. &lt;strong&gt;A common region of deletion on chromosome 17q in both sporadic and familial epithelial ovarian tumors distal to BRCA1.&lt;/strong&gt; Am. J. Hum. Genet. 55: 666-677, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7942844/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7942844&lt;/a&gt;]" pmid="7942844">Godwin et al. (1994)</a> examined normal and tumor DNA samples from 32 patients with sporadic and 8 patients with familial forms of epithelial ovarian tumors. Evaluation of a set of markers positioned telomeric to BRCA1 on chromosome 17q21 resulted in the highest degree of LOH, 73% (29/40), indicating that a candidate locus involved in ovarian cancer may reside distal to the BRCA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7942844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Russell, S. E. H., McIlhatton, M. A., Burrows, J. F., Donaghy, P. G., Chanduloy, S., Petty, E. M., Kalikin, L. M., Church, S. W., McIlroy, S., Harkin, D. P., Keilty, G. W., Cranston, A. N., Weissenbach, J., Hickey, I., Johnston, P. G. &lt;strong&gt;Isolation and mapping of a human septin gene to a region on chromosome 17q, commonly deleted in sporadic epithelial ovarian tumors.&lt;/strong&gt; Cancer Res. 60: 4729-4734, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10987277/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10987277&lt;/a&gt;]" pmid="10987277">Russell et al. (2000)</a> isolated the SEPT9 gene, which they designated ovarian/breast (Ov/Br) septin, as a candidate for the ovarian tumor suppressor gene that had been indirectly identified by up to 70% LOH for a marker at chromosome 17q25 in a bank of malignant ovarian tumors. Two splice variants were demonstrated within the 200-kb contig, which differed only at exon 1. The septins are a family of genes involved in cytokinesis and cell cycle control, whose known functions are consistent with the hypothesis that the human 17q25 septin gene may be a candidate for the ovarian tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10987277" 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="#37" class="mim-tip-reference" title="Rafnar, T., Gudbjartsson, D. F., Sulem, P., Jonasdottir, A., Sigurdsson, A., Jonasdottir, A., Besenbacher, S., Lundin, P., Stacey, S. N., Gudmundsson, J., Magnusson, O. T., le Roux, L., and 33 others. &lt;strong&gt;Mutations in BRIP1 confer high risk of ovarian cancer.&lt;/strong&gt; Nature Genet. 43: 1104-1107, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21964575/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21964575&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.955&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21964575">Rafnar et al. (2011)</a> performed a genomewide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders and imputed genotypes to 41,675 Icelanders using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer in 656 affected individuals. <a href="#37" class="mim-tip-reference" title="Rafnar, T., Gudbjartsson, D. F., Sulem, P., Jonasdottir, A., Sigurdsson, A., Jonasdottir, A., Besenbacher, S., Lundin, P., Stacey, S. N., Gudmundsson, J., Magnusson, O. T., le Roux, L., and 33 others. &lt;strong&gt;Mutations in BRIP1 confer high risk of ovarian cancer.&lt;/strong&gt; Nature Genet. 43: 1104-1107, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21964575/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21964575&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.955&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21964575">Rafnar et al. (2011)</a> discovered a rare (0.41% allelic frequency) frameshift mutation, 2040_2041insTT, in the BRIP1 (also known as FANCJ; <a href="/entry/605882">605882</a>) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, p = 2.8 x 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced life span by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, 1702_1703del, was seen in 2 of 144 subjects with ovarian cancer and 1 of 1,780 control subjects (p = 0.016). This allele was also associated with breast cancer (seen in 6 of 927 cases; p = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation showed loss of the wildtype allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964575" 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 id="molecularGenetics" class="mim-anchor"></a>
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Molecular Genetics</strong>
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<p><strong><em>Germline Mutations</em></strong></p><p>
<a href="#47" class="mim-tip-reference" title="Stratton, J. F., Thompson, D., Bobrow, L., Dalal, N., Gore, M., Bishop, D. T., Scott, I., Evans, G., Daly, P., Easton, D. F., Ponder, B. A. J. &lt;strong&gt;The genetic epidemiology of early-onset epithelial ovarian cancer: a population-based study.&lt;/strong&gt; Am. J. Hum. Genet. 65: 1725-1732, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10577927/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10577927&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302671&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10577927">Stratton et al. (1999)</a> conducted a population-based study to determine the contribution of germline mutations in known candidate genes to epithelial ovarian cancer diagnosed before the age of 30 years. Two of 101 women with invasive ovarian cancer had germline mutations in the MLH1 gene (<a href="/entry/120436">120436</a>), which is involved in hereditary nonpolyposis colorectal cancer-2 (HNPCC2; <a href="/entry/609310">609310</a>). In addition to colon cancer, ovarian cancer may be a manifestation of this syndrome. No germline mutations were identified in any of the other genes analyzed, including BRCA1, the 'ovarian cancer-cluster region' (nucleotides 3139-7069) of BRCA2, and MSH2. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or HNPCC. There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk = 1.6, P = 0.01), but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had an increased risk of ovarian cancer, myeloma, and non-Hodgkin lymphoma. The data indicated that germline mutations in BRCA1, BRCA2, MSH2, and MLH1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10577927" 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="#28" class="mim-tip-reference" title="Liede, A., Tonin, P. N., Sun, C. C., Serruya, C., Daly, M. B., Narod, S. A., Foulkes, W. D. &lt;strong&gt;Is hereditary site-specific ovarian cancer a distinct genetic condition?&lt;/strong&gt; Am. J. Med. Genet. 75: 55-58, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9450858/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9450858&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19980106)75:1&lt;55::aid-ajmg12&gt;3.0.co;2-r&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9450858">Liede et al. (1998)</a> raised the question of the existence of hereditary site-specific ovarian cancer as a genetic entity distinct from hereditary breast-ovarian cancer syndrome. They identified a large Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases of breast cancer. However, in all but 1 of the ovarian cancer cases, the 185delAG mutation in the BRCA1 gene (<a href="/entry/113705#0003">113705.0003</a>) segregated with the cancer. <a href="#28" class="mim-tip-reference" title="Liede, A., Tonin, P. N., Sun, C. C., Serruya, C., Daly, M. B., Narod, S. A., Foulkes, W. D. &lt;strong&gt;Is hereditary site-specific ovarian cancer a distinct genetic condition?&lt;/strong&gt; Am. J. Med. Genet. 75: 55-58, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9450858/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9450858&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19980106)75:1&lt;55::aid-ajmg12&gt;3.0.co;2-r&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9450858">Liede et al. (1998)</a> concluded that site-specific ovarian cancer families probably represent a variant of the breast-ovarian cancer syndrome, attributable to mutation in either BRCA1 or BRCA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9450858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutations</em></strong></p><p>
<a href="#4" class="mim-tip-reference" title="Cesari, R., Martin, E. S., Calin, G. A., Pentimalli, F., Bichi, R., McAdams, H., Trapasso, F., Drusco, A., Shimizu, M., Masciullo, V., d&#x27;Andrilli, G., Scambia, G., Picchio, M. C., Alder, H., Godwin, A. K., Croce, C. M. &lt;strong&gt;Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27.&lt;/strong&gt; Proc. Nat. Acad. Sci. 100: 5956-5961, 2003. Note: Editorial Expression of Concern: Proc. Nat. Acad. Sci. 114: E3364, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12719539/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12719539&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12719539[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0931262100&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12719539">Cesari et al. (2003)</a> identified the complete PARK2 gene (<a href="/entry/602544">602544</a>) within an LOH region on chromosome 6q25-q27. LOH analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50%) and D6S1599 (32%), both of which are located within the PARK2 gene. Expression of the PARK2 gene appeared to be downregulated or absent in the tumor biopsies and tumor cell lines examined. In addition, <a href="#4" class="mim-tip-reference" title="Cesari, R., Martin, E. S., Calin, G. A., Pentimalli, F., Bichi, R., McAdams, H., Trapasso, F., Drusco, A., Shimizu, M., Masciullo, V., d&#x27;Andrilli, G., Scambia, G., Picchio, M. C., Alder, H., Godwin, A. K., Croce, C. M. &lt;strong&gt;Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27.&lt;/strong&gt; Proc. Nat. Acad. Sci. 100: 5956-5961, 2003. Note: Editorial Expression of Concern: Proc. Nat. Acad. Sci. 114: E3364, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12719539/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12719539&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12719539[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0931262100&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12719539">Cesari et al. (2003)</a> found 2 somatic truncating deletions in the PARK2 gene (see, e.g., <a href="/entry/602544#0016">602544.0016</a>) in 3 of 20 ovarian cancers. The data suggested that PARK2 may act as a tumor suppressor gene. Because PARK2 maps to FRA6E, one of the most active common fragile sites in the human genome (<a href="#43" class="mim-tip-reference" title="Smith, D. I., Huang, H., Wang, L. &lt;strong&gt;Common fragile sites and cancer (review).&lt;/strong&gt; Int. J. Oncol. 12: 187-196, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9454904/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9454904&lt;/a&gt;]" pmid="9454904">Smith et al., 1998</a>), it may represent another example of a large tumor suppressor gene, like FHIT (<a href="/entry/601153">601153</a>) and WWOX (<a href="/entry/605131">605131</a>), located at a common fragile site. An Editorial Expression of Concern was published regarding the article by <a href="#4" class="mim-tip-reference" title="Cesari, R., Martin, E. S., Calin, G. A., Pentimalli, F., Bichi, R., McAdams, H., Trapasso, F., Drusco, A., Shimizu, M., Masciullo, V., d&#x27;Andrilli, G., Scambia, G., Picchio, M. C., Alder, H., Godwin, A. K., Croce, C. M. &lt;strong&gt;Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27.&lt;/strong&gt; Proc. Nat. Acad. Sci. 100: 5956-5961, 2003. Note: Editorial Expression of Concern: Proc. Nat. Acad. Sci. 114: E3364, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12719539/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12719539&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12719539[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0931262100&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12719539">Cesari et al. (2003)</a> because it appeared that Figures 2a and 2b, beta-actin panel, had duplicated bands. The authors stated that 'because this issue was first raised more than 10 years after publication, the original data are not available to confirm whether an error was made in the figure construction' but that 'any error in figure construction does not affect their scientific conclusions.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12719539+9454904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Denison, S. R., Wang, F., Becker, N. A., Schule, B., Kock, N., Phillips, L. A., Klein, C., Smith, D. I. &lt;strong&gt;Alterations in the common fragile site gene Parkin in ovarian and other cancers.&lt;/strong&gt; Oncogene 22: 8370-8378, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14614460/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14614460&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.onc.1207072&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14614460">Denison et al. (2003)</a> found that 4 (66.7%) ovarian cancer cell lines and 4 (18.2%) primary ovarian tumors were heterozygous for the duplication or deletion of 1 or more exons in the PARK2 gene. Additionally, 3 of 23 (13%) nonovarian tumor-derived cell lines were found to have a duplication or deletion of 1 or more parkin exons. Diminished or absent parkin expression was observed in most of the ovarian cancer cell lines when studies with antibodies were performed. <a href="#9" class="mim-tip-reference" title="Denison, S. R., Wang, F., Becker, N. A., Schule, B., Kock, N., Phillips, L. A., Klein, C., Smith, D. I. &lt;strong&gt;Alterations in the common fragile site gene Parkin in ovarian and other cancers.&lt;/strong&gt; Oncogene 22: 8370-8378, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14614460/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14614460&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.onc.1207072&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14614460">Denison et al. (2003)</a> suggested that parkin may represent a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14614460" 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="#42" class="mim-tip-reference" title="Sellar, G. C., Watt, K. P., Rabiasz, G. J., Stronach, E. A., Li, L., Miller, E. P., Massie, C. E., Miller, J., Contreras-Moreira, B., Scott, D., Brown, I., Williams, A. R., Bates, P. A., Smyth, J. F., Gabra, H. &lt;strong&gt;OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer.&lt;/strong&gt; Nature Genet. 34: 337-343, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12819783/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12819783&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1183&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12819783">Sellar et al. (2003)</a> determined that D11S4085 on 11q25 is located in the second intron of the OPCML gene (<a href="/entry/600632">600632</a>). OPCML was frequently somatically inactivated in epithelial ovarian cancer tissue by allele loss and by CpG island methylation. OPCML has functional characteristics consistent with tumor suppressor gene properties both in vitro and in vivo. A somatic missense mutation from an individual with epithelial ovarian cancer showed clear evidence of loss of function (<a href="/entry/600632#0001">600632.0001</a>). These findings suggested that OPCML was an excellent candidate for an ovarian cancer tumor suppressor gene located on 11q25. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12819783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By examining DNA copy number of 283 known miRNA genes, <a href="#49" class="mim-tip-reference" title="Zhang, L., Huang, J., Yang, N., Greshock, J., Megraw, M. S., Giannakakis, A., Liang, S., Naylor, T. L., Barchetti, A., Ward, M. R., Yao, G., Medina, A., O&#x27;Brien-Jenkins, A., Katsaros, D., Hatzigeorgiou, A., Gimotty, P. A., Weber, B. L., Coukos, G. &lt;strong&gt;MicroRNAs exhibit high frequency genomic alterations in human cancer.&lt;/strong&gt; Proc. Nat. Acad. Sci. 103: 9136-9141, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16754881/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16754881&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16754881[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0508889103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16754881">Zhang et al. (2006)</a> found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (<a href="/entry/606241">606241</a>), AGO2 (EIF2C2; <a href="/entry/606229">606229</a>), and other miRNA-associated genes in these cancers. <a href="#49" class="mim-tip-reference" title="Zhang, L., Huang, J., Yang, N., Greshock, J., Megraw, M. S., Giannakakis, A., Liang, S., Naylor, T. L., Barchetti, A., Ward, M. R., Yao, G., Medina, A., O&#x27;Brien-Jenkins, A., Katsaros, D., Hatzigeorgiou, A., Gimotty, P. A., Weber, B. L., Coukos, G. &lt;strong&gt;MicroRNAs exhibit high frequency genomic alterations in human cancer.&lt;/strong&gt; Proc. Nat. Acad. Sci. 103: 9136-9141, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16754881/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16754881&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16754881[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0508889103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16754881">Zhang et al. (2006)</a> concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16754881" 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="#23" class="mim-tip-reference" title="Kan, Z., Jaiswal, B. S., Stinson, J., Janakiraman, V., Bhatt, D., Stern, H. M., Yue, P., Haverty, P. M., Bourgon, R., Zheng, J., Moorhead, M., Chaudhuri, S., and 20 others. &lt;strong&gt;Diverse somatic mutation patterns and pathway alterations in human cancers.&lt;/strong&gt; Nature 466: 869-873, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20668451/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20668451&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature09208&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20668451">Kan et al. (2010)</a> reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. <a href="#23" class="mim-tip-reference" title="Kan, Z., Jaiswal, B. S., Stinson, J., Janakiraman, V., Bhatt, D., Stern, H. M., Yue, P., Haverty, P. M., Bourgon, R., Zheng, J., Moorhead, M., Chaudhuri, S., and 20 others. &lt;strong&gt;Diverse somatic mutation patterns and pathway alterations in human cancers.&lt;/strong&gt; Nature 466: 869-873, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20668451/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20668451&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature09208&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20668451">Kan et al. (2010)</a> found that mutation rates and the sets of mutated genes varied substantially across tumor types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G protein-coupled receptors such as GRM8 (<a href="/entry/601116">601116</a>), BAI3 (<a href="/entry/602684">602684</a>), AGTRL1 (<a href="/entry/600052">600052</a>), and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS (see <a href="/entry/139320">139320</a>), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (<a href="/entry/139311">139311</a>) and mutant MAP2K4 (<a href="/entry/601335">601335</a>) in oncogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20668451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The <a href="#3" class="mim-tip-reference" title="Cancer Genome Atlas Research Network. &lt;strong&gt;Integrated genomic analyses of ovarian carcinoma.&lt;/strong&gt; Nature 474: 609-615, 2011. Note: Erratum: Nature 490: 292 only, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21720365/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21720365&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21720365[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature10166&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21720365">Cancer Genome Atlas Research Network (2011)</a> reported that high-grade serous ovarian cancer is characterized by TP53 (<a href="/entry/191170">191170</a>) mutations in almost all tumors (96% of 489 high-grade serous ovarian adenocarcinomas); low prevalence but statistically recurrent somatic mutations in 9 further genes including NF1 (<a href="/entry/613113">613113</a>), BRCA1 (<a href="/entry/113705">113705</a>), BRCA2 (<a href="/entry/600185">600185</a>), RB1 (<a href="/entry/614041">614041</a>), and CDK12 (<a href="/entry/615514">615514</a>); 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated 4 ovarian cancer transcriptional subtypes, 3 microRNA subtypes, 4 promoter methylation subtypes, and a transcriptional signature associated with survival duration, and shed new light on the impact that tumors with BRCA1/2 and CCNE1 (<a href="/entry/123837">123837</a>) aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumors analyzed, and that NOTCH (<a href="/entry/190198">190198</a>) and FOXM1 (<a href="/entry/602341">602341</a>) signaling are involved in serous ovarian cancer pathophysiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21720365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifier Genes</em></strong></p><p>
<a href="#36" class="mim-tip-reference" title="Quaye, L., Dafou, D., Ramus, S. J., Song, H., Gentry-Maharaj, A., Notaridou, M., Hogdall, E., Kjaer, S. K., Christensen, L., Hogdall, C., Easton, D. F., Jacobs, I., Menon, U., Pharoah, P. D. P., Gayther, S. A. &lt;strong&gt;Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival.&lt;/strong&gt; Hum. Molec. Genet. 18: 1869-1878, 2009. Note: Erratum: Hum. Molec. Genet. 18: 2928 only, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19270026/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19270026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19270026">Quaye et al. (2009)</a> used microcell-mediated chromosome transfer approach and expression microarray analysis to identify candidate genes that were associated with neoplastic suppression in ovarian cancer cell lines. In over 1,600 ovarian cancer patients from 3 European population-based studies, they genotyped 68 tagging SNPs from 9 candidate genes and found a significant association between survival and 2 tagging SNPs in the RBBP8 gene (<a href="/entry/604124">604124</a>), <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4474794;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4474794</a> (hazard ratio, 0.85; 95% CI, 0.75-0.95; p = 0.007) and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9304261;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs9304261</a> (hazard ratio, 0.83; 95% CI, 0.71-0.95; p = 0.009). Loss of heterozygosity (LOH) analysis of tagging SNPs in 314 ovarian tumors identified associations between somatic gene deletions and survival. Thirty-five percent of tumors in 101 informative cases showed LOH for the RBBP8 gene, which was associated with a significantly worse prognosis (hazard ratio, 2.19; 95% CI, 1.36-3.54; p = 0.001). <a href="#36" class="mim-tip-reference" title="Quaye, L., Dafou, D., Ramus, S. J., Song, H., Gentry-Maharaj, A., Notaridou, M., Hogdall, E., Kjaer, S. K., Christensen, L., Hogdall, C., Easton, D. F., Jacobs, I., Menon, U., Pharoah, P. D. P., Gayther, S. A. &lt;strong&gt;Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival.&lt;/strong&gt; Hum. Molec. Genet. 18: 1869-1878, 2009. Note: Erratum: Hum. Molec. Genet. 18: 2928 only, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19270026/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19270026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19270026">Quaye et al. (2009)</a> concluded that germline genetic variation and somatic alterations of the RBBP8 gene in tumors are associated with survival in ovarian cancer patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19270026" 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 id="clinicalManagement" class="mim-anchor"></a>
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<p><a href="#7" class="mim-tip-reference" title="Chien, J., Aletti, G., Baldi, A., Catalano, V., Muretto, P., Keeney, G. L., Kalli, K. R., Staub, J., Ehrmann, M., Cliby, W. A., Lee, Y. K., Bible, K. C., Hartmann, L. C., Kaufmann, S. H., Shridhar, V. &lt;strong&gt;Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity.&lt;/strong&gt; J. Clin. Invest. 116: 1994-2004, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16767218/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16767218&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16767218[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI27698&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16767218">Chien et al. (2006)</a> studied HTRA1 (PRSS11; <a href="/entry/602194">602194</a>) expression in tumors from 60 patients with epithelial ovarian cancer and 51 with gastric cancer (<a href="/entry/137215">137215</a>) and found that those with tumors expressing higher levels of HTRA1 showed a significantly higher response rate to chemotherapy than those with lower levels of HTRA1 expression. <a href="#7" class="mim-tip-reference" title="Chien, J., Aletti, G., Baldi, A., Catalano, V., Muretto, P., Keeney, G. L., Kalli, K. R., Staub, J., Ehrmann, M., Cliby, W. A., Lee, Y. K., Bible, K. C., Hartmann, L. C., Kaufmann, S. H., Shridhar, V. &lt;strong&gt;Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity.&lt;/strong&gt; J. Clin. Invest. 116: 1994-2004, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16767218/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16767218&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16767218[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI27698&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16767218">Chien et al. (2006)</a> suggested that loss of HTRA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16767218" 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>Using a PCR-based differential display method, <a href="#32" class="mim-tip-reference" title="Mok, S. C., Wong, K.-K., Chan, R. K. W., Lau, C. C., Tsao, S.-W., Knapp, R. C., Berkowitz, R. S. &lt;strong&gt;Molecular cloning of differentially expressed genes in human epithelial ovarian cancer.&lt;/strong&gt; Gynecol. Oncol. 52: 247-252, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8314147/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8314147&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/gyno.1994.1040&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8314147">Mok et al. (1994)</a> identified a gene, termed DOC2 (<a href="/entry/601236">601236</a>), that was expressed in normal ovarian epithelial cells, but downregulated or absent from ovarian carcinoma cell lines. The DOC2 gene maps to chromosome 5p13. <a href="#31" class="mim-tip-reference" title="Mok, S. C., Chan, W. Y., Wong, K. K., Cheung, K. K., Lau, C. C., Ng, S. W., Baldini, A., Colitti, C. V., Rock, C. O., Berkowitz, R. S. &lt;strong&gt;DOC-2, a candidate tumor suppressor gene in human epithelial ovarian cancer.&lt;/strong&gt; Oncogene 16: 2381-2387, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9620555/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9620555&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.onc.1201769&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9620555">Mok et al. (1998)</a> reported that transfection of the DOC2 gene into an ovarian carcinoma cell line resulted in significantly reduced growth rate and ability to form tumors in nude mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9620555+8314147" 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>Among 48 primary ovarian cancer tumors and corresponding metastases, <a href="#2" class="mim-tip-reference" title="Blechschmidt, K., Sassen, S., Schmalfeldt, B., Schuster, T., Hofler, H., Becker, K.-F. &lt;strong&gt;The E-cadherin repressor snail is associated with lower overall survival of ovarian cancer patients.&lt;/strong&gt; Brit. J. Cancer 98: 489-495, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18026186/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18026186&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18026186[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.bjc.6604115&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18026186">Blechschmidt et al. (2008)</a> found a significant association (p = 0.008) between reduced E-cadherin (CDH1) expression in the primary cancer tissue and shorter overall survival. Patients with decreased E-cadherin expression and increased SNAIL (SNAI1; <a href="/entry/604238">604238</a>) expression in the primary tumor showed a higher risk of death (p = 0.002). There was no significant difference in expression of E-cadherin or SNAIL between primary tumors and metastases. The findings were consistent with a role for E-cadherin and SNAIL in the behavior of metastatic cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18026186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Merritt, W. M., Lin, Y. G., Han, L. Y., Kamat, A. A., Spannuth, W. A., Schmandt, R., Urbauer, D., Pennacchio, L. A., Cheng, J.-F., Nick, A. M., Deavers, M. T., Mourad-Zeidan, A., and 10 others. &lt;strong&gt;Dicer, Drosha, and outcomes in patients with ovarian cancer.&lt;/strong&gt; New Eng. J. Med. 359: 2641-2650, 2008. Note: Erratum: New Eng. J. Med. 363: 1877 only, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19092150/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19092150&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19092150[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa0803785&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19092150">Merritt et al. (2008)</a> observed decreased mRNA and protein expression of the RNAse III enzymes DICER1 (<a href="/entry/606241">606241</a>) and DROSHA (RNASEN; <a href="/entry/608828">608828</a>) in 60 and 51%, respectively, of 111 invasive epithelial ovarian cancer specimens. Low DICER1 expression was significantly associated with advanced tumor stage (p = 0.007), and low DROSHA expression with suboptimal surgical cytoreduction (p = 0.02). Cancer specimens with both high DICER1 expression and high DROSHA expression were associated with increased median survival (greater than 11 years vs 2.66 years for other subgroups; p less than 0.001). Statistical analysis revealed 3 independent predictors of reduced disease-specific survival: low DICER1 expression (hazard ratio, 2.10; p = 0.02), high-grade histologic features (hazard ratio, 2.46; p = 0.03), and poor response to chemotherapy (hazard ratio, 3.95; p less than 0.001). Poor clinical outcomes among patients with low DICER1 expression were validated in an additional cohort of patients. Although rare missense variants were found in both genes, the presence or absence did not correlate with the level of expression. Functional assays indicated that gene silencing with shRNA, but not siRNA, may be impaired in cells with low DICER1 expression. The findings implicated a component of the RNA-interference machinery, which regulates gene expression, in the pathogenesis of ovarian cancer. <a href="#30" class="mim-tip-reference" title="Merritt, W. M., Urbauer, D. L., Sood, A. K. &lt;strong&gt;Reply to Kobel et al. (Letter)&lt;/strong&gt; New Eng. J. Med. 360: 1151 only, 2009."None>Merritt et al. (2009)</a> noted that 109 of the 111 samples used in the 2008 study had serous histologic features, of which 93 were high-grade and 16 low-grade tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19092150" 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 explore the genetic origin of ovarian clear cell carcinoma, <a href="#21" class="mim-tip-reference" title="Jones, S., Wang, T.-L., Shih, I.-M., Mao, T.-L., Nakayama, K., Roden, R., Glas, R., Slamon, D., Diaz, L. A., Jr., Vogelstein, B., Kinzler, K. W., Velculescu, V. E., Papadopoulos, N. &lt;strong&gt;Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.&lt;/strong&gt; Science 330: 228-231, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20826764/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20826764&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1196333&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20826764">Jones et al. (2010)</a> determined the exomic sequences of 8 tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, <a href="#21" class="mim-tip-reference" title="Jones, S., Wang, T.-L., Shih, I.-M., Mao, T.-L., Nakayama, K., Roden, R., Glas, R., Slamon, D., Diaz, L. A., Jr., Vogelstein, B., Kinzler, K. W., Velculescu, V. E., Papadopoulos, N. &lt;strong&gt;Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.&lt;/strong&gt; Science 330: 228-231, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20826764/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20826764&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1196333&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20826764">Jones et al. (2010)</a> identified 4 genes that were mutated in at least 2 tumors. PIK3CA (<a href="/entry/171834">171834</a>), which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS (<a href="/entry/190070">190070</a>), which encodes a well-known oncoprotein, had previously been implicated in ovarian clear cell carcinoma. The other 2 mutated genes were previously unknown to be involved in ovarian clear cell carcinoma: PPP2R1A (<a href="/entry/605983">605983</a>) encodes a regulatory subunit of serine/threonine phosphatase-2, and ARID1A (<a href="/entry/603024">603024</a>) encodes adenine-thymine (AT)-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. The nature and pattern of the mutations suggested that PPP2R1A functions as an oncogene and ARID1A as a tumor suppressor gene. In a total of 42 ovarian clear cell carcinomas, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. <a href="#21" class="mim-tip-reference" title="Jones, S., Wang, T.-L., Shih, I.-M., Mao, T.-L., Nakayama, K., Roden, R., Glas, R., Slamon, D., Diaz, L. A., Jr., Vogelstein, B., Kinzler, K. W., Velculescu, V. E., Papadopoulos, N. &lt;strong&gt;Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.&lt;/strong&gt; Science 330: 228-231, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20826764/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20826764&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1196333&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20826764">Jones et al. (2010)</a> concluded that their results suggested that aberrant chromatin remodeling contributes to the pathogenesis of ovarian clear cell carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20826764" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Flesken-Nikitin, A., Hwang, C.-I., Cheng, C.-Y., Michurina, T. V., Enikolopov, G., Nikitin, A. Y. &lt;strong&gt;Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche.&lt;/strong&gt; Nature 495: 241-245, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23467088/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23467088&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23467088[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature11979&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23467088">Flesken-Nikitin et al. (2013)</a> identified the hilum region of the mouse ovary, the transitional (or junction) area between the ovarian surface epithelium, mesothelium, and tubal (oviductal) epithelium, as a stem cell niche of the ovarian surface epithelium (OSE). They found that cells of the hilum OSE are cycling slowly and express stem and/or progenitor cell markers ALDH1 (<a href="/entry/100640">100640</a>), LGR5 (<a href="/entry/606667">606667</a>), LEF1 (<a href="/entry/153245">153245</a>), CD133 (<a href="/entry/604365">604365</a>), and CK6B (<a href="/entry/148042">148042</a>). These cells display long-term stem cell properties ex vivo and in vivo, as shown by serial sphere generation and long-term lineage-tracing assays. Importantly, the hilum cells showed increased transformation potential after inactivation of tumor suppressor genes Trp53 (<a href="/entry/191170">191170</a>) and Rb1 (<a href="/entry/614041">614041</a>), whose pathways are altered frequently in the most aggressive and common type of human epithelial ovarian cancer, high-grade serous adenocarcinoma. <a href="#15" class="mim-tip-reference" title="Flesken-Nikitin, A., Hwang, C.-I., Cheng, C.-Y., Michurina, T. V., Enikolopov, G., Nikitin, A. Y. &lt;strong&gt;Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche.&lt;/strong&gt; Nature 495: 241-245, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23467088/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23467088&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23467088[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature11979&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23467088">Flesken-Nikitin et al. (2013)</a> concluded that their study supported experimentally the idea that susceptibility of transitional zones to malignant transformation may be explained by the presence of stem cell niches in these areas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23467088" 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 better understand the drivers of clinical phenotypes of high-grade serous ovarian cancer, <a href="#33" class="mim-tip-reference" title="Patch, A.-M., Christie, E. L., Etemadmoghadam, D., Garsed, D. W., George, J., Fereday, S., Nones, K., Cowin, P., Alsop, K., Bailey, P. J., Kassahn, K. S., Newell, F., and 71 others. &lt;strong&gt;Whole-genome characterization of chemoresistant ovarian cancer.&lt;/strong&gt; Nature 521: 489-494, 2015. Note: Erratum: Nature 527: 398 only, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26017449/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26017449&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature14410&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26017449">Patch et al. (2015)</a> used whole-genome sequencing of tumor and germline DNA samples from 92 patients with primary refractory, resistant, sensitive, and matched acquired resistant disease. The authors showed that gene breakage commonly inactivates the tumor suppressors RB1, NF1 (<a href="/entry/613113">613113</a>), RAD51B (<a href="/entry/602948">602948</a>), and PTEN (<a href="/entry/601728">601728</a>) in high-grade serous ovarian cancer, contributing to acquired chemotherapy resistance. CCNE1 (<a href="/entry/123837">123837</a>) amplification was common in primary resistant and refractory disease. <a href="#33" class="mim-tip-reference" title="Patch, A.-M., Christie, E. L., Etemadmoghadam, D., Garsed, D. W., George, J., Fereday, S., Nones, K., Cowin, P., Alsop, K., Bailey, P. J., Kassahn, K. S., Newell, F., and 71 others. &lt;strong&gt;Whole-genome characterization of chemoresistant ovarian cancer.&lt;/strong&gt; Nature 521: 489-494, 2015. Note: Erratum: Nature 527: 398 only, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26017449/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26017449&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature14410&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26017449">Patch et al. (2015)</a> observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 (<a href="/entry/113705">113705</a>) or BRCA2 (<a href="/entry/600185">600185</a>) mutations in individual patients; loss of BRCA1 promoter methylation; an alteration in molecular subtype; and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1 (<a href="/entry/171050">171050</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26017449" 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="#14" class="mim-tip-reference" title="Eckert, M. A., Coscia, F., Chryplewicz, A., Chang, J. W., Hernandez, K. M., Pan, S., Tienda, S. M., Nahotko, D. A., Li, G., Blazenovic, I., Lastra, R. R., Curtis, M., Yamada, S. D., Perets, R., McGregor, S. M., Andrade, J., Fiehn, O., Moellering, R. E., Mann, M., Lengyel, E. &lt;strong&gt;Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts.&lt;/strong&gt; Nature 569: 723-728, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31043742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31043742&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31043742[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41586-019-1173-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31043742">Eckert et al. (2019)</a> developed a label-free proteomic workflow to analyze as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from both the tumor and stromal compartments of ovarian cancer. The tumor proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT; <a href="/entry/600008">600008</a>) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation, and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumor stroma. <a href="#14" class="mim-tip-reference" title="Eckert, M. A., Coscia, F., Chryplewicz, A., Chang, J. W., Hernandez, K. M., Pan, S., Tienda, S. M., Nahotko, D. A., Li, G., Blazenovic, I., Lastra, R. R., Curtis, M., Yamada, S. D., Perets, R., McGregor, S. M., Andrade, J., Fiehn, O., Moellering, R. E., Mann, M., Lengyel, E. &lt;strong&gt;Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts.&lt;/strong&gt; Nature 569: 723-728, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31043742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31043742&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31043742[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41586-019-1173-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31043742">Eckert et al. (2019)</a> concluded that NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31043742" 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 id="genotypePhenotypeCorrelations" class="mim-anchor"></a>
<h4 href="#mimGenotypePhenotypeCorrelationsFold" id="mimGenotypePhenotypeCorrelationsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p><a href="#18" class="mim-tip-reference" title="Grindedal, E. M., Renkonen-Sinisalo, L., Vasen, H., Evans, G., Sala, P., Blanco, I., Gronwald, J., Apold, J., Eccles, D. M., Sanchez, A. A., Sampson, J., Jarvinen, H. J., Bertario, L., Crawford, G. C., Stormorken, A. T., Maehle, L., Moller, P. &lt;strong&gt;Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds.&lt;/strong&gt; J. Med. Genet. 47: 99-102, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19635727/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19635727&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2009.068130&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19635727">Grindedal et al. (2010)</a> performed a retrospective survival study of 144 women with ovarian cancer due to MMR mutations. Fifty-one (35.4%) had a mutation in MLH1, 78 (54.2%) had a mutation in MSH2, and 15 (10.4%) had a mutation in MSH6. The mean age of onset was 44.7 years, compared to 51.2 years in carriers of BRCA1 mutations with ovarian cancer and 57.5 in carriers of BRCA2 mutations with ovarian cancer (<a href="#38" class="mim-tip-reference" title="Risch, H. A., McLaughlin, J. R., Cole, D. E. C., Rosen, B., Bradley, L., Kwan, E., Jack, E., Vesprini, D. J., Kuperstein, G., Abrahamson, J. L. A., Fan, I., Wong, B., Narod, S. A. &lt;strong&gt;Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.&lt;/strong&gt; Am. J. Hum. Genet. 68: 700-710, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11179017/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11179017&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/318787&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11179017">Risch et al., 2001</a>). Most (81.5%) women with MMR mutations were diagnosed at stage 1 or 2. Twenty-nine (20.1%) of 144 woman with MMR-related ovarian cancer died of their ovarian cancer. The 5-, 10-, 20- and 30-year survival specific for deaths due to ovarian cancers were 82.7%, 80.6%, 78.0% and 71.5%, respectively. About 50% of the women developed another cancer in the HNPCC/Lynch syndrome tumor spectrum. The 5-, 10-, 20-, and 30-year survival specific for deaths due to HNPCC/Lynch syndrome-associated cancers were 79.2%, 75.7%, 68.4% and 47.3%, respectively. Overall, the survival for women with ovarian cancer due to MMR mutations was better than for those with ovarian cancer due to BRCA1/2 mutations, which is less than 40% at 10 years. The lifetime risk of ovarian cancer in MMR mutation carriers was about 10% and the risk of dying from ovarian cancer was 20%, yielding an overall risk of dying from ovarian cancer of about 2% in MMR mutation carriers. <a href="#18" class="mim-tip-reference" title="Grindedal, E. M., Renkonen-Sinisalo, L., Vasen, H., Evans, G., Sala, P., Blanco, I., Gronwald, J., Apold, J., Eccles, D. M., Sanchez, A. A., Sampson, J., Jarvinen, H. J., Bertario, L., Crawford, G. C., Stormorken, A. T., Maehle, L., Moller, P. &lt;strong&gt;Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds.&lt;/strong&gt; J. Med. Genet. 47: 99-102, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19635727/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19635727&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2009.068130&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19635727">Grindedal et al. (2010)</a> suggested that mutations in the MMR and BRCA1/2 genes may predispose to biologically different types of tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11179017+19635727" 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>Animal Model</strong>
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<p><a href="#10" class="mim-tip-reference" title="Dinulescu, D. M., Ince, T. A., Quade, B. J., Shafer, S. A., Crowley, D., Jacks, T. &lt;strong&gt;Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer.&lt;/strong&gt; Nature Med. 11: 63-70, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15619626/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15619626&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm1173&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15619626">Dinulescu et al. (2005)</a> developed a mouse model of ovarian cancer. A recombinant adenoviral vector expressing an oncogenic Kras (<a href="/entry/190070">190070</a>) allele within the ovarian surface epithelium resulted in the development of benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma; 7 of 15 mice (47%) also developed peritoneal endometriosis (<a href="/entry/131200">131200</a>). When the Kras mutation was combined with conditional deletion of Pten (<a href="/entry/601728">601728</a>), all mice developed invasive endometrioid ovarian adenocarcinomas. <a href="#10" class="mim-tip-reference" title="Dinulescu, D. M., Ince, T. A., Quade, B. J., Shafer, S. A., Crowley, D., Jacks, T. &lt;strong&gt;Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer.&lt;/strong&gt; Nature Med. 11: 63-70, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15619626/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15619626&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm1173&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15619626">Dinulescu et al. (2005)</a> stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15619626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="seeAlso" class="mim-anchor"></a>
<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>See Also:</strong>
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<span class="mim-text-font">
<a href="#Donnai1983" class="mim-tip-reference" title="Donnai, D., Warrell, D. W. &lt;strong&gt;Familial ovarian cancer: gynaecological and genetic management.&lt;/strong&gt; J. Med. Genet. 20: 300 only, 1983.">Donnai and Warrell (1983)</a>
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<a id="references"class="mim-anchor"></a>
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<span class="mim-font">
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<strong>REFERENCES</strong>
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</h4>
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<ol>
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<a id="1" class="mim-anchor"></a>
<a id="Auersperg2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Auersperg, N., Wong, A. S. T., Choi, K.-C., Kang, S. K., Leung, P. C. K.
<strong>Ovarian surface epithelium: biology, endocrinology, and pathology.</strong>
Endocr. Rev. 22: 255-288, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11294827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11294827</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11294827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/edrv.22.2.0422" target="_blank">Full Text</a>]
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<a id="Blechschmidt2008" class="mim-anchor"></a>
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<p class="mim-text-font">
Blechschmidt, K., Sassen, S., Schmalfeldt, B., Schuster, T., Hofler, H., Becker, K.-F.
<strong>The E-cadherin repressor snail is associated with lower overall survival of ovarian cancer patients.</strong>
Brit. J. Cancer 98: 489-495, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18026186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18026186</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18026186[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=18026186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/sj.bjc.6604115" target="_blank">Full Text</a>]
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<a id="{Cancer Genome Atlas Research Network}2011" class="mim-anchor"></a>
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<p class="mim-text-font">
Cancer Genome Atlas Research Network.
<strong>Integrated genomic analyses of ovarian carcinoma.</strong>
Nature 474: 609-615, 2011. Note: Erratum: Nature 490: 292 only, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21720365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21720365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21720365[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=21720365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nature10166" target="_blank">Full Text</a>]
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<a id="Cesari2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Cesari, R., Martin, E. S., Calin, G. A., Pentimalli, F., Bichi, R., McAdams, H., Trapasso, F., Drusco, A., Shimizu, M., Masciullo, V., d'Andrilli, G., Scambia, G., Picchio, M. C., Alder, H., Godwin, A. K., Croce, C. M.
<strong>Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27.</strong>
Proc. Nat. Acad. Sci. 100: 5956-5961, 2003. Note: Editorial Expression of Concern: Proc. Nat. Acad. Sci. 114: E3364, 2017.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12719539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12719539</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12719539[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=12719539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.0931262100" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
<a id="Chenevix-Trench1994" class="mim-anchor"></a>
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Chenevix-Trench, G., Kerr, J., Friedlander, M., Hurst, T., Sanderson, B., Coglan, M., Ward, B., Leary, J., Khoo, S.-K.
<strong>Homozygous deletions on the short arm of chromosome 9 in ovarian adenocarcinoma cell lines and loss of heterozygosity in sporadic tumors.</strong>
Am. J. Hum. Genet. 55: 143-149, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8023842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8023842</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8023842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="6" class="mim-anchor"></a>
<a id="Chi2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Chi, D. S., Liao, J. B., Leon, L. F., Venkatraman, E. S., Hensley, M. L., Bhaskaran, D., Hoskins, W. J.
<strong>Identification of prognostic factors in advanced epithelial ovarian carcinoma.</strong>
Gynec. Oncol. 82: 532-537, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11520151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11520151</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11520151" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1006/gyno.2001.6328" target="_blank">Full Text</a>]
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<a id="Chien2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Chien, J., Aletti, G., Baldi, A., Catalano, V., Muretto, P., Keeney, G. L., Kalli, K. R., Staub, J., Ehrmann, M., Cliby, W. A., Lee, Y. K., Bible, K. C., Hartmann, L. C., Kaufmann, S. H., Shridhar, V.
<strong>Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity.</strong>
J. Clin. Invest. 116: 1994-2004, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16767218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16767218</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16767218[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=16767218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI27698" target="_blank">Full Text</a>]
</p>
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<a id="8" class="mim-anchor"></a>
<a id="Colitti1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Colitti, C. V., Rodabaugh, K. J., Welch, W. R., Berkowitz, R. S., Mok, S. C.
<strong>A novel 4 cM minimal deletion unit on chromosome 6q25.1-q25.2 associated with high grade invasive epithelial ovarian carcinomas.</strong>
Oncogene 16: 555-559, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9484846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9484846</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9484846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/sj.onc.1201523" target="_blank">Full Text</a>]
</p>
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<a id="9" class="mim-anchor"></a>
<a id="Denison2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Denison, S. R., Wang, F., Becker, N. A., Schule, B., Kock, N., Phillips, L. A., Klein, C., Smith, D. I.
<strong>Alterations in the common fragile site gene Parkin in ovarian and other cancers.</strong>
Oncogene 22: 8370-8378, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14614460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14614460</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14614460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/sj.onc.1207072" target="_blank">Full Text</a>]
</p>
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<a id="Patch2015" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Patch, A.-M., Christie, E. L., Etemadmoghadam, D., Garsed, D. W., George, J., Fereday, S., Nones, K., Cowin, P., Alsop, K., Bailey, P. J., Kassahn, K. S., Newell, F., and 71 others.
<strong>Whole-genome characterization of chemoresistant ovarian cancer.</strong>
Nature 521: 489-494, 2015. Note: Erratum: Nature 527: 398 only, 2015.
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[<a href="https://doi.org/10.1038/nature14410" target="_blank">Full Text</a>]
</p>
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<a id="34" class="mim-anchor"></a>
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Philipp, E. E.
<strong>Familial carcinoma of the ovary: case report.</strong>
Brit. J. Obstet. Gynaec. 86: 152-153, 1979.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/427055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">427055</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=427055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1471-0528.1979.tb10584.x" target="_blank">Full Text</a>]
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<p class="mim-text-font">
Phillips, N. J., Zeigler, M. R., Deaven, L. L.
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[<a href="https://doi.org/10.1016/0304-3835(96)04169-9" target="_blank">Full Text</a>]
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<a id="Quaye2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Quaye, L., Dafou, D., Ramus, S. J., Song, H., Gentry-Maharaj, A., Notaridou, M., Hogdall, E., Kjaer, S. K., Christensen, L., Hogdall, C., Easton, D. F., Jacobs, I., Menon, U., Pharoah, P. D. P., Gayther, S. A.
<strong>Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddp107" target="_blank">Full Text</a>]
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<a id="37" class="mim-anchor"></a>
<a id="Rafnar2011" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rafnar, T., Gudbjartsson, D. F., Sulem, P., Jonasdottir, A., Sigurdsson, A., Jonasdottir, A., Besenbacher, S., Lundin, P., Stacey, S. N., Gudmundsson, J., Magnusson, O. T., le Roux, L., and 33 others.
<strong>Mutations in BRIP1 confer high risk of ovarian cancer.</strong>
Nature Genet. 43: 1104-1107, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964575</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng.955" target="_blank">Full Text</a>]
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<a id="38" class="mim-anchor"></a>
<a id="Risch2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Risch, H. A., McLaughlin, J. R., Cole, D. E. C., Rosen, B., Bradley, L., Kwan, E., Jack, E., Vesprini, D. J., Kuperstein, G., Abrahamson, J. L. A., Fan, I., Wong, B., Narod, S. A.
<strong>Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.</strong>
Am. J. Hum. Genet. 68: 700-710, 2001.
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[<a href="https://doi.org/10.1086/318787" target="_blank">Full Text</a>]
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<a id="Russell2000" class="mim-anchor"></a>
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Russell, S. E. H., McIlhatton, M. A., Burrows, J. F., Donaghy, P. G., Chanduloy, S., Petty, E. M., Kalikin, L. M., Church, S. W., McIlroy, S., Harkin, D. P., Keilty, G. W., Cranston, A. N., Weissenbach, J., Hickey, I., Johnston, P. G.
<strong>Isolation and mapping of a human septin gene to a region on chromosome 17q, commonly deleted in sporadic epithelial ovarian tumors.</strong>
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<a id="40" class="mim-anchor"></a>
<a id="Saito1992" class="mim-anchor"></a>
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<p class="mim-text-font">
Saito, S., Saito, H., Koi, S., Sagae, S., Kudo, R., Saito, J., Noda, K., Nakamura, Y.
<strong>Fine-scale deletion mapping of the distal long arm of chromosome 6 in 70 human ovarian cancers.</strong>
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</p>
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<a id="41" class="mim-anchor"></a>
<a id="Schultz1996" class="mim-anchor"></a>
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<p class="mim-text-font">
Schultz, D. C., Vanderveer, L., Berman, D. B., Hamilton, T. C., Wong, A. J., Godwin, A. K.
<strong>Identification of two candidate tumor suppressor genes on chromosome 17p13.3.</strong>
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</p>
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<a id="42" class="mim-anchor"></a>
<a id="Sellar2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Sellar, G. C., Watt, K. P., Rabiasz, G. J., Stronach, E. A., Li, L., Miller, E. P., Massie, C. E., Miller, J., Contreras-Moreira, B., Scott, D., Brown, I., Williams, A. R., Bates, P. A., Smyth, J. F., Gabra, H.
<strong>OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer.</strong>
Nature Genet. 34: 337-343, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12819783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12819783</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12819783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1183" target="_blank">Full Text</a>]
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<a id="43" class="mim-anchor"></a>
<a id="Smith1998" class="mim-anchor"></a>
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<p class="mim-text-font">
Smith, D. I., Huang, H., Wang, L.
<strong>Common fragile sites and cancer (review).</strong>
Int. J. Oncol. 12: 187-196, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9454904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9454904</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9454904" 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="44" class="mim-anchor"></a>
<a id="Song2009" class="mim-anchor"></a>
<div class="">
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Song, H., Ramus, S. J., Kjaer, S. K., DiCioccio, R. A., Chenevix-Trench, G., Pearce, C. L., Hogdall, E., Whittemore, A. S., McGuire, V., Hogdall, C., Blaakaer, J., Wu, A. H., and 39 others.
<strong>Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study.</strong>
Hum. Molec. Genet. 18: 2297-2304, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19304784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19304784</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19304784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/ddp138" target="_blank">Full Text</a>]
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<a id="45" class="mim-anchor"></a>
<a id="Soslow2008" class="mim-anchor"></a>
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Soslow, R. A.
<strong>Histologic subtypes of ovarian carcinoma: an overview.</strong>
Int. J. Gynec. Path. 27: 161-174, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18317227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18317227</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18317227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/PGP.0b013e31815ea812" target="_blank">Full Text</a>]
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<a id="46" class="mim-anchor"></a>
<a id="Stany2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Stany, M. P., Bonome, T., Wamunyokoli, F., Zorn, K., Ozbun, L., Park, D.-C., Hao, K., Boyd, J., Sood, A. K., Gershenson, D. M., Berkowitz, R. S., Mok, S. C., Birrer, M. J.
<strong>Classification of ovarian cancer: a genomic analysis.</strong>
Adv. Exp. Med. Biol. 622: 23-33, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18546616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18546616</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18546616[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=18546616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/978-0-387-68969-2_3" target="_blank">Full Text</a>]
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<a id="47" class="mim-anchor"></a>
<a id="Stratton1999" class="mim-anchor"></a>
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Stratton, J. F., Thompson, D., Bobrow, L., Dalal, N., Gore, M., Bishop, D. T., Scott, I., Evans, G., Daly, P., Easton, D. F., Ponder, B. A. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577927</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10577927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/302671" target="_blank">Full Text</a>]
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<a id="48" class="mim-anchor"></a>
<a id="Whang-Peng1984" class="mim-anchor"></a>
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Whang-Peng, J., Knutsen, T., Douglass, E. C., Chu, E., Ozols, R. F., Hogan, W. M., Young, R. C.
<strong>Cytogenetic studies in ovarian cancer.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6690026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6690026</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6690026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0165-4608(84)90102-x" target="_blank">Full Text</a>]
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Zhang, L., Huang, J., Yang, N., Greshock, J., Megraw, M. S., Giannakakis, A., Liang, S., Naylor, T. L., Barchetti, A., Ward, M. R., Yao, G., Medina, A., O'Brien-Jenkins, A., Katsaros, D., Hatzigeorgiou, A., Gimotty, P. A., Weber, B. L., Coukos, G.
<strong>MicroRNAs exhibit high frequency genomic alterations in human cancer.</strong>
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[<a href="https://doi.org/10.1073/pnas.0508889103" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 12/20/2019
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Ada Hamosh - updated : 06/24/2015<br>Ada Hamosh - updated : 4/1/2013<br>Ada Hamosh - updated : 7/26/2012<br>Ada Hamosh - updated : 7/23/2012<br>Ada Hamosh - updated : 8/24/2011<br>Ada Hamosh - updated : 11/4/2010<br>Ada Hamosh - updated : 9/21/2010<br>Cassandra L. Kniffin - updated : 6/4/2010<br>George E. Tiller - updated : 3/2/2010<br>George E. Tiller - updated : 2/22/2010<br>Cassandra L. Kniffin - updated : 3/19/2009<br>Cassandra L. Kniffin - reorganized : 2/6/2009<br>Cassandra L. Kniffin - updated : 1/30/2009<br>Victor A. McKusick - updated : 3/13/1998<br>Victor A. McKusick - updated : 2/24/1998
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Victor A. McKusick : 6/2/1986
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<strong>#</strong> 167000
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<h3>
<span class="mim-font">
OVARIAN CANCER
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</h3>
</div>
<div>
<br />
</div>
<div>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
OVARIAN CANCER, EPITHELIAL, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<p>
<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 363443007; &nbsp;
<strong>ICD10CM:</strong> C56; &nbsp;
<strong>ICD9CM:</strong> 183.0; &nbsp;
<strong>DO:</strong> 2394; &nbsp;
</span>
</p>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
3p22.1
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
167000
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
CTNNB1
</span>
</td>
<td>
<span class="mim-font">
116806
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
3q26.32
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
167000
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
PIK3CA
</span>
</td>
<td>
<span class="mim-font">
171834
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
6q26
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
167000
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
PRKN
</span>
</td>
<td>
<span class="mim-font">
602544
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
11q25
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
167000
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
OPCML
</span>
</td>
<td>
<span class="mim-font">
600632
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
14q32.33
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
167000
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
AKT1
</span>
</td>
<td>
<span class="mim-font">
164730
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
16q22.1
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
167000
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
CDH1
</span>
</td>
<td>
<span class="mim-font">
192090
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
17q12
</span>
</td>
<td>
<span class="mim-font">
Ovarian cancer, somatic
</span>
</td>
<td>
<span class="mim-font">
167000
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
ERBB2
</span>
</td>
<td>
<span class="mim-font">
164870
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because ovarian cancer has been associated with somatic changes in several genes, including OPCML (600632), PIK3CA (171834), AKT1 (164730), CTNNB1 (116806), RRAS2 (600098), CDH1 (192090), ERBB2 (164870), and PARK2 (602544).</p><p>See also 607893 for an ovarian cancer susceptibility locus (OVCAS1) that has been mapped to chromosome 3p25-p22.</p><p>Familial ovarian cancer may be part of other cancer syndromes. See susceptibility to familial breast-ovarian cancer 1 and 2 (604370 and 612555), due to mutations in the BRCA1 (113705) and BRCA2 (600185) genes, respectively; and Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (see, e.g., HNPCC1; 120435), due to mutations in DNA mismatch repair genes such as MSH2 (609309), MSH3 (600887), MSH6 (600678), and MLH1 (120436).</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (Chi et al., 2001). These typical features relate to the biology of the disease, which is a principal determinant of outcome (Auersperg et al., 2001). Epithelial ovarian cancer is the most common form and encompasses 5 major histologic subtypes: papillary serous, endometrioid, mucinous, clear cell, and transitional cell. Epithelial ovarian cancer arises as a result of genetic alterations sustained by the ovarian surface epithelium (Stany et al., 2008; Soslow, 2008). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>There are several early reports of familial ovarian cancer showing autosomal dominant inheritance. Some of these families may have had the breast-ovarian cancer syndrome or Lynch syndrome. Liber (1950) described a family with histologically proven papillary adenocarcinoma of the ovary in 5 sisters and their mother. Jackson (1967) reported a Jamaican family in which grandmother, mother, and daughter developed ovarian tumors; 2 tumors were known to have been dysgerminomas (see 603737). Lewis and Davison (1969) described a family in which 5 of 6 sisters and their mother had ovarian cancer. One of the 5 had a malignant ovarian cyst but subsequently died of colon cancer. Prophylactic oophorectomy was performed in the sixth sister and in 5 females of the following generation. </p><p>Li et al. (1970) reported a family in which 7 women, including 4 sisters, had ovarian carcinoma. Ovarian cancer was suspected in 3 other women of the family. Philipp (1979) described a family with multiple cases of poorly differentiated cystadenocarcinoma of the ovary. The 4 relatives with ovarian carcinoma were the proband's mother, maternal aunt, that woman's daughter, and the daughter of another maternal aunt. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Cytogenetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Whang-Peng et al. (1984) performed cytogenetic studies on ovarian tumor tissue from 44 patients with various forms of epithelial ovarian cancer. All 44 samples had numerical abnormalities, and 39 had structural abnormalities involving multiple chromosomes. Clone formation and the number of chromosomes involved in structural abnormalities increased with duration of disease and were more extensive in patients treated with chemotherapy compared to patients treated with surgery alone. Aneuploidy was observed in all patients and there was considerable variation in the chromosome numbers, often ranging from diploidy to triploidy to tetraploidy. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Chromosome 2q22.1</em></strong></p><p>
Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, Song et al. (2009) evaluated 11 of the most significant loci from a previously reported breast cancer genomewide association study for association with invasive ovarian cancer (Easton et al., 2007). The 11 SNPs were initially genotyped in 2,927 invasive ovarian cancer cases and 4,143 controls from 6 ovarian cancer case-control studies. Only rs4954956 located less than 7.0 kb upstream of the NXPH2 gene (604635) was significantly associated with ovarian cancer risk both in the replication study and in combined analysis of 5,353 patients and 8,453 controls. This association was stronger for the serous histologic subtype (p = 0.0004; OR, 1.14) than for all types of ovarian cancer (p = 0.05; OR, 1.07). </p><p><strong><em>Chromosome 6q25</em></strong></p><p>
Saito et al. (1992) examined loss of heterozygosity (LOH) in 70 ovarian tumors using 9 RFLP markers located at chromosome 6q24-q27. Among 33 informative serous cancers, 17 (52%) showed allelic loss at a few or all loci examined, whereas only 1 of 15 mucinous-type tumors and 2 of 12 clear-cell tumors showed LOH. A detailed deletion map delineated a 1.9-cM region, within which the authors postulated the existence of a tumor suppressor gene involved in ovarian carcinoma. </p><p>In 54 fresh and paraffin-embedded invasive ovarian epithelial tumor tissues, Colitti et al. (1998) used tandem repeat markers on chromosome 6q25 to delineate a 4-cM minimal region of LOH of 6q25.1-q25.2 between markers D6S473 and D6S448. Loss of heterozygosity was observed more frequently at the loci defined by marker D6S473 (14 of 32 informative cases, 44%) and marker D6S448 (17 of 40 informative cases, 43%). LOH at D6S473 correlated significantly both with serous compared to non-serous ovarian tumors (p = 0.040), and with high-grade compared to low-grade specimens (p = 0.023). </p><p><strong><em>Chromosome 9p24</em></strong></p><p>
By transfection of NIH-3T3 cells with genomic DNA from a human ovarian adenocarcinoma tumor cell line, Halverson et al. (1990) identified a rearranged human DNA sequence that was generated during transfection and induced both morphologic transformation and tumorigenesis. One fragment mapped to human chromosome 9p24 and the other to human chromosome 8. Because rat ovarian surface epithelial cells transformed spontaneously in vitro have been found to have homozygous deletions of the interferon alpha gene (IFNA; 147660) on 9p22, suggesting inactivation of a tumor-suppressor gene in that region may be crucial for the development of ovarian cancer, Chenevix-Trench et al. (1994) used microsatellite markers and Southern analysis to examine the homologous region in humans, 9p, for deletions in sporadic ovarian adenocarcinomas and ovarian tumor cell lines. Loss of heterozygosity occurred in 34 (37%) of 91 informative sporadic tumors, including some benign, low-malignant-potential and early-stage tumors, suggesting that it is an early event in the development of ovarian adenocarcinoma. Furthermore, homozygous deletions on 9p were found in 2 of 10 independent cell lines. Deletion mapping of the tumors and cell lines indicated that the candidate suppressor gene inactivated as a consequence lies between D9S171 and the IFNA locus. This region is deleted in several other tumors and contains a melanoma predisposition locus (155601). In a note added in proof, Chenevix-Trench et al. (1994) suggested that the target of these 9p deletions might be CDKN2 (600160) as described by Kamb et al. (1994). </p><p><strong><em>Chromosome 11q25</em></strong></p><p>
Loss of heterozygosity studies indicated that a tumor suppressor gene associated with sporadic ovarian cancer may reside at chromosome 11q25 (Gabra et al., 1996; Launonen et al., 1998). In tumor tissue from 118 individuals with epithelial ovarian cancer, Sellar et al. (2003) observed a peak LOH rate of 49% (36 of 74 informative cases) across 11q25 at D11S4085. Conversely, LOH analysis of 39 pairs of DNA from individuals with colorectal cancer (see 114500) and normal DNA showed an LOH rate at D11S4085 of only 23% (6 of 26 informative cases), with no evidence of complete LOH. </p><p><strong><em>Chromosome 17p</em></strong></p><p>
Eccles et al. (1990) found LOH of chromosome 17p in 69% of 16 epithelial ovarian cancer tumors. </p><p>Schultz et al. (1996) identified 2 genes, OVCA1 (DPH1; 603527) and OVCA2 (607896), within a minimum region of allelic loss on chromosome 17p13.3 in a cohort of ovarian tumors. Expression of OVCA1 and OVCA2 was reduced or undetectable in ovarian tumor tissue and cell lines compared with normal ovarian epithelial cells. The findings provided evidence for 1 or more possible tumor suppressor genes on chromosome 17p distinct from the TP53 gene (191170). </p><p>Phillips et al. (1996) also identified the DPH1 (OVCA1) gene within the region on chromosome 17p13.3 that is deleted in 80% of all ovarian epithelial malignancies. They suggested that it may act as a tumor suppressor gene. </p><p><strong><em>Chromosome 17q</em></strong></p><p>
Chromosome 17q contains several genes implicated in ovarian cancer: the BRCA1 gene (113705) on 17q21, the ERBB2 gene (164870) on 17q21.1, and the SEPT9 gene (604061) on 17q25.</p><p>Eccles et al. (1990) found LOH of 17q in 77% of 16 epithelial ovarian cancer tumors. </p><p>Godwin et al. (1994) examined normal and tumor DNA samples from 32 patients with sporadic and 8 patients with familial forms of epithelial ovarian tumors. Evaluation of a set of markers positioned telomeric to BRCA1 on chromosome 17q21 resulted in the highest degree of LOH, 73% (29/40), indicating that a candidate locus involved in ovarian cancer may reside distal to the BRCA1 gene. </p><p>Russell et al. (2000) isolated the SEPT9 gene, which they designated ovarian/breast (Ov/Br) septin, as a candidate for the ovarian tumor suppressor gene that had been indirectly identified by up to 70% LOH for a marker at chromosome 17q25 in a bank of malignant ovarian tumors. Two splice variants were demonstrated within the 200-kb contig, which differed only at exon 1. The septins are a family of genes involved in cytokinesis and cell cycle control, whose known functions are consistent with the hypothesis that the human 17q25 septin gene may be a candidate for the ovarian tumor suppressor gene. </p><p>Rafnar et al. (2011) performed a genomewide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders and imputed genotypes to 41,675 Icelanders using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer in 656 affected individuals. Rafnar et al. (2011) discovered a rare (0.41% allelic frequency) frameshift mutation, 2040_2041insTT, in the BRIP1 (also known as FANCJ; 605882) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, p = 2.8 x 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced life span by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, 1702_1703del, was seen in 2 of 144 subjects with ovarian cancer and 1 of 1,780 control subjects (p = 0.016). This allele was also associated with breast cancer (seen in 6 of 927 cases; p = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation showed loss of the wildtype allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Germline Mutations</em></strong></p><p>
Stratton et al. (1999) conducted a population-based study to determine the contribution of germline mutations in known candidate genes to epithelial ovarian cancer diagnosed before the age of 30 years. Two of 101 women with invasive ovarian cancer had germline mutations in the MLH1 gene (120436), which is involved in hereditary nonpolyposis colorectal cancer-2 (HNPCC2; 609310). In addition to colon cancer, ovarian cancer may be a manifestation of this syndrome. No germline mutations were identified in any of the other genes analyzed, including BRCA1, the 'ovarian cancer-cluster region' (nucleotides 3139-7069) of BRCA2, and MSH2. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or HNPCC. There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk = 1.6, P = 0.01), but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had an increased risk of ovarian cancer, myeloma, and non-Hodgkin lymphoma. The data indicated that germline mutations in BRCA1, BRCA2, MSH2, and MLH1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. </p><p>Liede et al. (1998) raised the question of the existence of hereditary site-specific ovarian cancer as a genetic entity distinct from hereditary breast-ovarian cancer syndrome. They identified a large Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases of breast cancer. However, in all but 1 of the ovarian cancer cases, the 185delAG mutation in the BRCA1 gene (113705.0003) segregated with the cancer. Liede et al. (1998) concluded that site-specific ovarian cancer families probably represent a variant of the breast-ovarian cancer syndrome, attributable to mutation in either BRCA1 or BRCA2. </p><p><strong><em>Somatic Mutations</em></strong></p><p>
Cesari et al. (2003) identified the complete PARK2 gene (602544) within an LOH region on chromosome 6q25-q27. LOH analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50%) and D6S1599 (32%), both of which are located within the PARK2 gene. Expression of the PARK2 gene appeared to be downregulated or absent in the tumor biopsies and tumor cell lines examined. In addition, Cesari et al. (2003) found 2 somatic truncating deletions in the PARK2 gene (see, e.g., 602544.0016) in 3 of 20 ovarian cancers. The data suggested that PARK2 may act as a tumor suppressor gene. Because PARK2 maps to FRA6E, one of the most active common fragile sites in the human genome (Smith et al., 1998), it may represent another example of a large tumor suppressor gene, like FHIT (601153) and WWOX (605131), located at a common fragile site. An Editorial Expression of Concern was published regarding the article by Cesari et al. (2003) because it appeared that Figures 2a and 2b, beta-actin panel, had duplicated bands. The authors stated that 'because this issue was first raised more than 10 years after publication, the original data are not available to confirm whether an error was made in the figure construction' but that 'any error in figure construction does not affect their scientific conclusions.' </p><p>Denison et al. (2003) found that 4 (66.7%) ovarian cancer cell lines and 4 (18.2%) primary ovarian tumors were heterozygous for the duplication or deletion of 1 or more exons in the PARK2 gene. Additionally, 3 of 23 (13%) nonovarian tumor-derived cell lines were found to have a duplication or deletion of 1 or more parkin exons. Diminished or absent parkin expression was observed in most of the ovarian cancer cell lines when studies with antibodies were performed. Denison et al. (2003) suggested that parkin may represent a tumor suppressor gene. </p><p>Sellar et al. (2003) determined that D11S4085 on 11q25 is located in the second intron of the OPCML gene (600632). OPCML was frequently somatically inactivated in epithelial ovarian cancer tissue by allele loss and by CpG island methylation. OPCML has functional characteristics consistent with tumor suppressor gene properties both in vitro and in vivo. A somatic missense mutation from an individual with epithelial ovarian cancer showed clear evidence of loss of function (600632.0001). These findings suggested that OPCML was an excellent candidate for an ovarian cancer tumor suppressor gene located on 11q25. </p><p>By examining DNA copy number of 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types. </p><p>Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Kan et al. (2010) found that mutation rates and the sets of mutated genes varied substantially across tumor types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G protein-coupled receptors such as GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335) in oncogenesis. </p><p>The Cancer Genome Atlas Research Network (2011) reported that high-grade serous ovarian cancer is characterized by TP53 (191170) mutations in almost all tumors (96% of 489 high-grade serous ovarian adenocarcinomas); low prevalence but statistically recurrent somatic mutations in 9 further genes including NF1 (613113), BRCA1 (113705), BRCA2 (600185), RB1 (614041), and CDK12 (615514); 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated 4 ovarian cancer transcriptional subtypes, 3 microRNA subtypes, 4 promoter methylation subtypes, and a transcriptional signature associated with survival duration, and shed new light on the impact that tumors with BRCA1/2 and CCNE1 (123837) aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumors analyzed, and that NOTCH (190198) and FOXM1 (602341) signaling are involved in serous ovarian cancer pathophysiology. </p><p><strong><em>Modifier Genes</em></strong></p><p>
Quaye et al. (2009) used microcell-mediated chromosome transfer approach and expression microarray analysis to identify candidate genes that were associated with neoplastic suppression in ovarian cancer cell lines. In over 1,600 ovarian cancer patients from 3 European population-based studies, they genotyped 68 tagging SNPs from 9 candidate genes and found a significant association between survival and 2 tagging SNPs in the RBBP8 gene (604124), rs4474794 (hazard ratio, 0.85; 95% CI, 0.75-0.95; p = 0.007) and rs9304261 (hazard ratio, 0.83; 95% CI, 0.71-0.95; p = 0.009). Loss of heterozygosity (LOH) analysis of tagging SNPs in 314 ovarian tumors identified associations between somatic gene deletions and survival. Thirty-five percent of tumors in 101 informative cases showed LOH for the RBBP8 gene, which was associated with a significantly worse prognosis (hazard ratio, 2.19; 95% CI, 1.36-3.54; p = 0.001). Quaye et al. (2009) concluded that germline genetic variation and somatic alterations of the RBBP8 gene in tumors are associated with survival in ovarian cancer patients. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Chien et al. (2006) studied HTRA1 (PRSS11; 602194) expression in tumors from 60 patients with epithelial ovarian cancer and 51 with gastric cancer (137215) and found that those with tumors expressing higher levels of HTRA1 showed a significantly higher response rate to chemotherapy than those with lower levels of HTRA1 expression. Chien et al. (2006) suggested that loss of HTRA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Using a PCR-based differential display method, Mok et al. (1994) identified a gene, termed DOC2 (601236), that was expressed in normal ovarian epithelial cells, but downregulated or absent from ovarian carcinoma cell lines. The DOC2 gene maps to chromosome 5p13. Mok et al. (1998) reported that transfection of the DOC2 gene into an ovarian carcinoma cell line resulted in significantly reduced growth rate and ability to form tumors in nude mice. </p><p>Among 48 primary ovarian cancer tumors and corresponding metastases, Blechschmidt et al. (2008) found a significant association (p = 0.008) between reduced E-cadherin (CDH1) expression in the primary cancer tissue and shorter overall survival. Patients with decreased E-cadherin expression and increased SNAIL (SNAI1; 604238) expression in the primary tumor showed a higher risk of death (p = 0.002). There was no significant difference in expression of E-cadherin or SNAIL between primary tumors and metastases. The findings were consistent with a role for E-cadherin and SNAIL in the behavior of metastatic cancer. </p><p>Merritt et al. (2008) observed decreased mRNA and protein expression of the RNAse III enzymes DICER1 (606241) and DROSHA (RNASEN; 608828) in 60 and 51%, respectively, of 111 invasive epithelial ovarian cancer specimens. Low DICER1 expression was significantly associated with advanced tumor stage (p = 0.007), and low DROSHA expression with suboptimal surgical cytoreduction (p = 0.02). Cancer specimens with both high DICER1 expression and high DROSHA expression were associated with increased median survival (greater than 11 years vs 2.66 years for other subgroups; p less than 0.001). Statistical analysis revealed 3 independent predictors of reduced disease-specific survival: low DICER1 expression (hazard ratio, 2.10; p = 0.02), high-grade histologic features (hazard ratio, 2.46; p = 0.03), and poor response to chemotherapy (hazard ratio, 3.95; p less than 0.001). Poor clinical outcomes among patients with low DICER1 expression were validated in an additional cohort of patients. Although rare missense variants were found in both genes, the presence or absence did not correlate with the level of expression. Functional assays indicated that gene silencing with shRNA, but not siRNA, may be impaired in cells with low DICER1 expression. The findings implicated a component of the RNA-interference machinery, which regulates gene expression, in the pathogenesis of ovarian cancer. Merritt et al. (2009) noted that 109 of the 111 samples used in the 2008 study had serous histologic features, of which 93 were high-grade and 16 low-grade tumors. </p><p>To explore the genetic origin of ovarian clear cell carcinoma, Jones et al. (2010) determined the exomic sequences of 8 tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, Jones et al. (2010) identified 4 genes that were mutated in at least 2 tumors. PIK3CA (171834), which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS (190070), which encodes a well-known oncoprotein, had previously been implicated in ovarian clear cell carcinoma. The other 2 mutated genes were previously unknown to be involved in ovarian clear cell carcinoma: PPP2R1A (605983) encodes a regulatory subunit of serine/threonine phosphatase-2, and ARID1A (603024) encodes adenine-thymine (AT)-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. The nature and pattern of the mutations suggested that PPP2R1A functions as an oncogene and ARID1A as a tumor suppressor gene. In a total of 42 ovarian clear cell carcinomas, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. Jones et al. (2010) concluded that their results suggested that aberrant chromatin remodeling contributes to the pathogenesis of ovarian clear cell carcinoma. </p><p>Flesken-Nikitin et al. (2013) identified the hilum region of the mouse ovary, the transitional (or junction) area between the ovarian surface epithelium, mesothelium, and tubal (oviductal) epithelium, as a stem cell niche of the ovarian surface epithelium (OSE). They found that cells of the hilum OSE are cycling slowly and express stem and/or progenitor cell markers ALDH1 (100640), LGR5 (606667), LEF1 (153245), CD133 (604365), and CK6B (148042). These cells display long-term stem cell properties ex vivo and in vivo, as shown by serial sphere generation and long-term lineage-tracing assays. Importantly, the hilum cells showed increased transformation potential after inactivation of tumor suppressor genes Trp53 (191170) and Rb1 (614041), whose pathways are altered frequently in the most aggressive and common type of human epithelial ovarian cancer, high-grade serous adenocarcinoma. Flesken-Nikitin et al. (2013) concluded that their study supported experimentally the idea that susceptibility of transitional zones to malignant transformation may be explained by the presence of stem cell niches in these areas. </p><p>To better understand the drivers of clinical phenotypes of high-grade serous ovarian cancer, Patch et al. (2015) used whole-genome sequencing of tumor and germline DNA samples from 92 patients with primary refractory, resistant, sensitive, and matched acquired resistant disease. The authors showed that gene breakage commonly inactivates the tumor suppressors RB1, NF1 (613113), RAD51B (602948), and PTEN (601728) in high-grade serous ovarian cancer, contributing to acquired chemotherapy resistance. CCNE1 (123837) amplification was common in primary resistant and refractory disease. Patch et al. (2015) observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 (113705) or BRCA2 (600185) mutations in individual patients; loss of BRCA1 promoter methylation; an alteration in molecular subtype; and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1 (171050). </p><p>Eckert et al. (2019) developed a label-free proteomic workflow to analyze as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from both the tumor and stromal compartments of ovarian cancer. The tumor proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT; 600008) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation, and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumor stroma. Eckert et al. (2019) concluded that NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Grindedal et al. (2010) performed a retrospective survival study of 144 women with ovarian cancer due to MMR mutations. Fifty-one (35.4%) had a mutation in MLH1, 78 (54.2%) had a mutation in MSH2, and 15 (10.4%) had a mutation in MSH6. The mean age of onset was 44.7 years, compared to 51.2 years in carriers of BRCA1 mutations with ovarian cancer and 57.5 in carriers of BRCA2 mutations with ovarian cancer (Risch et al., 2001). Most (81.5%) women with MMR mutations were diagnosed at stage 1 or 2. Twenty-nine (20.1%) of 144 woman with MMR-related ovarian cancer died of their ovarian cancer. The 5-, 10-, 20- and 30-year survival specific for deaths due to ovarian cancers were 82.7%, 80.6%, 78.0% and 71.5%, respectively. About 50% of the women developed another cancer in the HNPCC/Lynch syndrome tumor spectrum. The 5-, 10-, 20-, and 30-year survival specific for deaths due to HNPCC/Lynch syndrome-associated cancers were 79.2%, 75.7%, 68.4% and 47.3%, respectively. Overall, the survival for women with ovarian cancer due to MMR mutations was better than for those with ovarian cancer due to BRCA1/2 mutations, which is less than 40% at 10 years. The lifetime risk of ovarian cancer in MMR mutation carriers was about 10% and the risk of dying from ovarian cancer was 20%, yielding an overall risk of dying from ovarian cancer of about 2% in MMR mutation carriers. Grindedal et al. (2010) suggested that mutations in the MMR and BRCA1/2 genes may predispose to biologically different types of tumors. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Dinulescu et al. (2005) developed a mouse model of ovarian cancer. A recombinant adenoviral vector expressing an oncogenic Kras (190070) allele within the ovarian surface epithelium resulted in the development of benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma; 7 of 15 mice (47%) also developed peritoneal endometriosis (131200). When the Kras mutation was combined with conditional deletion of Pten (601728), all mice developed invasive endometrioid ovarian adenocarcinomas. Dinulescu et al. (2005) stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Donnai and Warrell (1983)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
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Russell, S. E. H., McIlhatton, M. A., Burrows, J. F., Donaghy, P. G., Chanduloy, S., Petty, E. M., Kalikin, L. M., Church, S. W., McIlroy, S., Harkin, D. P., Keilty, G. W., Cranston, A. N., Weissenbach, J., Hickey, I., Johnston, P. G.
<strong>Isolation and mapping of a human septin gene to a region on chromosome 17q, commonly deleted in sporadic epithelial ovarian tumors.</strong>
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Saito, S., Saito, H., Koi, S., Sagae, S., Kudo, R., Saito, J., Noda, K., Nakamura, Y.
<strong>Fine-scale deletion mapping of the distal long arm of chromosome 6 in 70 human ovarian cancers.</strong>
Cancer Res. 52: 5815-5817, 1992.
[PubMed: 1394208]
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Schultz, D. C., Vanderveer, L., Berman, D. B., Hamilton, T. C., Wong, A. J., Godwin, A. K.
<strong>Identification of two candidate tumor suppressor genes on chromosome 17p13.3.</strong>
Cancer Res. 56: 1997-2002, 1996.
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Sellar, G. C., Watt, K. P., Rabiasz, G. J., Stronach, E. A., Li, L., Miller, E. P., Massie, C. E., Miller, J., Contreras-Moreira, B., Scott, D., Brown, I., Williams, A. R., Bates, P. A., Smyth, J. F., Gabra, H.
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Int. J. Oncol. 12: 187-196, 1998.
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Soslow, R. A.
<strong>Histologic subtypes of ovarian carcinoma: an overview.</strong>
Int. J. Gynec. Path. 27: 161-174, 2008.
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<strong>Cytogenetic studies in ovarian cancer.</strong>
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Ada Hamosh - updated : 12/20/2019<br>Ada Hamosh - updated : 06/24/2015<br>Ada Hamosh - updated : 4/1/2013<br>Ada Hamosh - updated : 7/26/2012<br>Ada Hamosh - updated : 7/23/2012<br>Ada Hamosh - updated : 8/24/2011<br>Ada Hamosh - updated : 11/4/2010<br>Ada Hamosh - updated : 9/21/2010<br>Cassandra L. Kniffin - updated : 6/4/2010<br>George E. Tiller - updated : 3/2/2010<br>George E. Tiller - updated : 2/22/2010<br>Cassandra L. Kniffin - updated : 3/19/2009<br>Cassandra L. Kniffin - reorganized : 2/6/2009<br>Cassandra L. Kniffin - updated : 1/30/2009<br>Victor A. McKusick - updated : 3/13/1998<br>Victor A. McKusick - updated : 2/24/1998
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Victor A. McKusick : 6/2/1986
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