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Entry
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- #114550 - HEPATOCELLULAR CARCINOMA
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- OMIM
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<p>
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<span class="h4">#114550</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/114550"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#pathogenesis">Pathogenesis</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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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=HEPATOCELLULAR CARCINOMA" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=18690&Typ=Pat" title="Adult hepatocellular carcinoma" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Adult hepatocellular carci… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=10320&Typ=Pat" title="Pediatric hepatocellular carcinoma" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pediatric hepatocellular c… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=836&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hepatoblastoma </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=11824&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hepatocellular carcinoma </a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/3338" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=114550[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=210159" title="Adult hepatocellular carcinoma" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Adult hepatocellular carci…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=33402" title="Pediatric hepatocellular carcinoma" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pediatric hepatocellular c…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hepatoblastoma</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=88673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hepatocellular carcinoma</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:684" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/114550" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA001990/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:684" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:114550" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 109841003, 1186630006, 187769009, 25370001, 93870000<br />
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<strong>ICD10CM:</strong> C22.0, C22.9<br />
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<strong>ICD9CM:</strong> 155.2<br />
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<strong>ORPHA:</strong> 210159, 33402, 449, 88673<br />
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<strong>DO:</strong> 684<br />
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">ICD+</a>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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114550
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</span>
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</span>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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HEPATOCELLULAR CARCINOMA
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</h3>
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</div>
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<div>
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<br />
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</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
HCC<br />
|
|
CANCER, HEPATOCELLULAR<br />
|
|
LIVER CANCER<br />
|
|
LIVER CELL CARCINOMA; LCC<br />
|
|
HEPATOMA
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</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">
|
|
HEPATOBLASTOMA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
HEPATOBLASTOMA CAUSED BY SOMATIC MUTATION, 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/2/914?start=-3&limit=10&highlight=914">
|
|
2q33.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114550"> 114550 </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">
|
|
CASP8
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601763"> 601763 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<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">
|
|
Hepatocellular carcinoma, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114550"> 114550 </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">
|
|
Hepatocellular carcinoma, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114550"> 114550 </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/5/369?start=-3&limit=10&highlight=369">
|
|
5q22.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatoblastoma, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114550"> 114550 </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">
|
|
APC
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611731"> 611731 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/6/999?start=-3&limit=10&highlight=999">
|
|
6q25.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114550"> 114550 </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">
|
|
IGF2R
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/147280"> 147280 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/604?start=-3&limit=10&highlight=604">
|
|
7q31.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, childhood type, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114550"> 114550 </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">
|
|
MET
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/164860"> 164860 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/8/79?start=-3&limit=10&highlight=79">
|
|
8p22
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular cancer, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114550"> 114550 </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">
|
|
PDGFRL
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604584"> 604584 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/24?start=-3&limit=10&highlight=24">
|
|
16p13.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114550"> 114550 </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">
|
|
AXIN1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603816"> 603816 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/175?start=-3&limit=10&highlight=175">
|
|
17p13.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114550"> 114550 </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">
|
|
TP53
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/191170"> 191170 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/114550" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/114550" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/114550" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<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>
|
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|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Liver </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<span class="mim-font">
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- Hepatocellular carcinoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/109841003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">109841003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/187769009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">187769009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1186630006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1186630006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25370001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25370001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C22.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C22.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2239176&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2239176</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001402" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001402</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001402" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001402</a>]</span><br /> -
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Micronodular cirrhosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/21861000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">21861000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0267812&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0267812</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001413" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001413</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001413" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001413</a>]</span><br /> -
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Subacute progressive viral hepatitis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861901&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861901</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006572</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006572</a>]</span><br />
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<strong> NEOPLASIA </strong>
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- Primary liver cancer <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95214007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95214007</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/155.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">155.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0024620&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024620</a>]</span><br />
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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- Often integrated HBV sequences in hepatocellular carcinomas <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861902&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861902</a>]</span><br />
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</span>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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<span class="mim-font">
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- Genetic heterogeneity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242960&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242960</a>]</span><br />
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Associated with mutation in the p53 tumor protein gene (TP53, <a href="/entry/191170#0006">191170.0006</a>)<br /> -
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Associated with mutation in the MET protooncogene (MET, <a href="/entry/164860#0008">164860.0008</a>)<br /> -
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Associated with mutation in the beta-1 catenin gene (CTNNB1, <a href="/entry/116806#0013">116806.0013</a>)<br />
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because somatic mutations in a number of different genes have been identified in hepatocellular carcinoma (HCC) and hepatoblastoma. These include TP53 (<a href="/entry/191170">191170</a>), MET (<a href="/entry/164860">164860</a>), CTNNB1 (<a href="/entry/116806">116806</a>), PIK3CA (<a href="/entry/171834">171834</a>), AXIN1 (<a href="/entry/603816">603816</a>), and APC (<a href="/entry/611731">611731</a>).</p><p>See <a href="/entry/142330">142330</a> for familial hepatic adenoma, sometimes associated with hepatocellular carcinoma.</p>
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<br />
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<a id="description" class="mim-anchor"></a>
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (<a href="#38" class="mim-tip-reference" title="Taniguchi, K., Roberts, L. R., Aderca, I. N., Dong, X., Qian, C., Murphy, L. M., Nagorney, D. M., Burgart, L. J., Roche, P. C., Smith, D. I., Ross, J. A., Liu, W. <strong>Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas.</strong> Oncogene 21: 4863-4871, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12101426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12101426</a>] [<a href="https://doi.org/10.1038/sj.onc.1205591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12101426">Taniguchi et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12101426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<br />
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Primary cancer of the liver in 3 brothers was described by <a href="#19" class="mim-tip-reference" title="Kaplan, L., Cole, L. <strong>Fraternal primary hepatocellular carcinoma in three male, adult siblings.</strong> Am. J. Med. 39: 305-311, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14320698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14320698</a>] [<a href="https://doi.org/10.1016/0002-9343(65)90056-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14320698">Kaplan and Cole (1965)</a> and by <a href="#10" class="mim-tip-reference" title="Hagstrom, R. M., Baker, T. D. <strong>Primary hepatocellular carcinoma in three male siblings.</strong> Cancer 22: 142-150, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4298178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4298178</a>] [<a href="https://doi.org/10.1002/1097-0142(196807)22:1<142::aid-cncr2820220117>3.0.co;2-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4298178">Hagstrom and Baker (1968)</a>. In these patients there was no recognized preexisting liver disease. <a href="#7" class="mim-tip-reference" title="Denison, E. K., Peters, R. L., Reynolds, T. B. <strong>Familial hepatoma with hepatitis-associated antigen.</strong> Ann. Intern. Med. 74: 391-394, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4324021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4324021</a>] [<a href="https://doi.org/10.7326/0003-4819-74-3-391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4324021">Denison et al. (1971)</a> described 2 adult brothers who died of primary hepatocellular carcinoma. Both had micronodular cirrhosis with features of subacute progressive viral hepatitis. Australia antigen was demonstrated in the brother in whom it was sought. Their father had died much earlier of hepatocellular carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14320698+4298178+4324021" 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>Hepatoblastoma has been described in sibs (<a href="#9" class="mim-tip-reference" title="Fraumeni, J. F., Rosen, P. J., Hull, E. W., Barth, R. F., Shapiro, S. R., O'Connor, J. F. <strong>Hepatoblastoma in infant sisters.</strong> Cancer 24: 1086-1090, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4311111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4311111</a>] [<a href="https://doi.org/10.1002/1097-0142(196911)24:5<1086::aid-cncr2820240535>3.0.co;2-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4311111">Fraumeni et al., 1969</a>; <a href="#27" class="mim-tip-reference" title="Napoli, V. M., Campbell, W. G., Jr. <strong>Hepatoblastoma in infant sister and brother.</strong> Cancer 39: 2647-2650, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/194674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">194674</a>] [<a href="https://doi.org/10.1002/1097-0142(197706)39:6<2647::aid-cncr2820390651>3.0.co;2-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="194674">Napoli and Campbell, 1977</a>; <a href="#16" class="mim-tip-reference" title="Ito, E., Sato, Y., Kawauchi, K., Munakata, H., Kamata, Y., Yodono, H., Yokoyama, M. <strong>Type 1a glycogen storage disease with hepatoblastoma in siblings.</strong> Cancer 59: 1776-1780, 1987. Note: Erratum: Cancer 60: 723 only, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3030527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3030527</a>] [<a href="https://doi.org/10.1002/1097-0142(19870515)59:10<1776::aid-cncr2820591016>3.0.co;2-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3030527">Ito et al., 1987</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3030527+4311111+194674" 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>See <a href="/entry/231100">231100</a> for description of liver cancer as a complication of giant cell hepatitis of infancy. Familial liver cell carcinoma might also have its explanation in alpha-1-antitrypsin deficiency (<a href="/entry/613490">613490</a>), hemochromatosis (<a href="/entry/235200">235200</a>), and tyrosinemia (<a href="/entry/276700">276700</a>).</p><p><a href="#18" class="mim-tip-reference" title="Jiang, Y., Sun, A., Zhao, Y., Ying, W., Sun, H., Yang, X., Xing, B., Sun, W., Ren, L., Hu, B., Li, C., Zhang, L., and 27 others. <strong>Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma.</strong> Nature 567: 257-261, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30814741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30814741</a>] [<a href="https://doi.org/10.1038/s41586-019-0987-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30814741">Jiang et al. (2019)</a> used proteomic and phosphoproteomic profiling to characterize 110 paired tumor and nontumor tissues of clinical early-stage hepatocellular carcinoma related to hepatitis B virus infection. The quantitative proteomic data highlight heterogeneity in early-stage hepatocellular carcinoma. The cohort was stratified into subtypes S-I, S-II, and S-III, each of which has a different clinical outcome. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30814741" 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>Other Features</strong>
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<p><a href="#40" class="mim-tip-reference" title="Wang, C., Vegna, S., Jin, H., Benedict, B., Lieftink, C., Ramirez, C., de Oliveira, R. L., Morris, B., Gadiot, J., Wang, W., du Chatinier, A., Wang, L., and 13 others. <strong>Inducing and exploiting vulnerabilities for the treatment of liver cancer.</strong> Nature 574: 268-272, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31578521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31578521</a>] [<a href="https://doi.org/10.1038/s41586-019-1607-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31578521">Wang et al. (2019)</a> used a kinome-focused genetic screen to show that pharmacologic inhibition of the DNA-replication kinase CDC7 (603311) induces senescence selectively in liver cancer cells with mutations in TP53 (<a href="/entry/191170">191170</a>). A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR (<a href="/entry/601231">601231</a>) signaling, and selective drugs that targeted this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signaling after its inhibition was blocked in cells that had been treated with a CDC7 inhibitor, which led to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, <a href="#40" class="mim-tip-reference" title="Wang, C., Vegna, S., Jin, H., Benedict, B., Lieftink, C., Ramirez, C., de Oliveira, R. L., Morris, B., Gadiot, J., Wang, W., du Chatinier, A., Wang, L., and 13 others. <strong>Inducing and exploiting vulnerabilities for the treatment of liver cancer.</strong> Nature 574: 268-272, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31578521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31578521</a>] [<a href="https://doi.org/10.1038/s41586-019-1607-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31578521">Wang et al. (2019)</a> showed that treatment with combined inhibition of CDC7 and mTOR resulted in a marked reduction of tumor growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31578521" 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>Somatic Mutations</em></strong></p><p>
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<a href="#28" class="mim-tip-reference" title="Oda, H., Imai, Y., Nakatsuru, Y., Hata, J., Ishikawa, T. <strong>Somatic mutations of the APC gene in sporadic hepatoblastomas.</strong> Cancer Res. 56: 3320-3323, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8764128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8764128</a>]" pmid="8764128">Oda et al. (1996)</a> observed loss of heterozygosity (LOH) at the APC and/or MCC (<a href="/entry/159350">159350</a>) loci in 4 (57%) of 7 informative hepatoblastoma tissues. Somatic mutations were detected in 8 (61.5%) of the 13 total cases, with 9 cases (69%) showing genetic alterations in the APC gene as LOH or somatic mutations (see, e.g., <a href="/entry/611731#0024">611731.0024</a>). Double mutations were demonstrated in 2 cases. The nature of the somatic mutations observed in this study was unusual because 9 of the 10 mutations were missense, with only 1 case featuring a frameshift mutation due to an insertion. By contrast, more than 90% of mutations in the APC gene in colorectal tumors result in a truncated APC protein due to either frameshift or nonsense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8764128" 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="Thorgeirsson, S. S., Grisham, J. W. <strong>Molecular pathogenesis of human hepatocellular carcinoma.</strong> Nature Genet. 31: 339-346, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149612</a>] [<a href="https://doi.org/10.1038/ng0802-339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12149612">Thorgeirsson and Grisham (2002)</a> reviewed the molecular pathogenesis of HCC. The malignant phenotype is heterogeneous, and is produced by the disruption of a number of genes that function in different regulatory pathways, producing several molecular variants of HCC. The authors diagrammed the chronologic sequence of cellular events starting with chronic hepatitis from hepatitis B virus (HBV), hepatitis C virus (HCV), and AFB1, which together are responsible for approximately 80% of all HCCS in humans, and proceeding through successive steps of dysplasia and neoplasia. They diagrammed 11 autosome arms in 9 different chromosomes that have been found to contain allelic deletions in more than 30% of reported HCC. Other autosome arms contain allelic deletions in more than 20% of HCC. Heterogeneity of genomic aberrations may reflect the actions of different causative agents. A notable example of an aberration in gene structure related to a specific cause of HCCs is high frequency of the mutation arg249 to ser (<a href="/entry/191170#0006">191170.0006</a>) of p53 in the tumors of patients chronically exposed to AFB. <a href="#39" class="mim-tip-reference" title="Thorgeirsson, S. S., Grisham, J. W. <strong>Molecular pathogenesis of human hepatocellular carcinoma.</strong> Nature Genet. 31: 339-346, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149612</a>] [<a href="https://doi.org/10.1038/ng0802-339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12149612">Thorgeirsson and Grisham (2002)</a> tabulated 14 genes affected by loss of heterozygosity (LOH), mutation, or both in more than 15% of HCCs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12149612" 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>Activation of wingless (Wnt) signaling through mutations in beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>) contributes to the development of HCC and hepatoblastoma (review by <a href="#38" class="mim-tip-reference" title="Taniguchi, K., Roberts, L. R., Aderca, I. N., Dong, X., Qian, C., Murphy, L. M., Nagorney, D. M., Burgart, L. J., Roche, P. C., Smith, D. I., Ross, J. A., Liu, W. <strong>Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas.</strong> Oncogene 21: 4863-4871, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12101426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12101426</a>] [<a href="https://doi.org/10.1038/sj.onc.1205591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12101426">Taniguchi et al., 2002</a>). To explore the contribution of additional Wnt pathway molecules to hepatocarcinogenesis, <a href="#38" class="mim-tip-reference" title="Taniguchi, K., Roberts, L. R., Aderca, I. N., Dong, X., Qian, C., Murphy, L. M., Nagorney, D. M., Burgart, L. J., Roche, P. C., Smith, D. I., Ross, J. A., Liu, W. <strong>Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas.</strong> Oncogene 21: 4863-4871, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12101426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12101426</a>] [<a href="https://doi.org/10.1038/sj.onc.1205591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12101426">Taniguchi et al. (2002)</a> examined CTNNB1 mutations and mutations in AXIN1 (<a href="/entry/603816">603816</a>) and AXIN2 (<a href="/entry/604025">604025</a>) in 73 HCCs and 27 hepatoblastomas. Beta-catenin mutations were detected in 19.2% (14 of 73) HCCs and 70.4% (19 of 27) hepatoblastomas. Beta-catenin mutations in HCCs were primarily point mutations, whereas more than half of the hepatoblastomas had deletions. AXIN1 mutations occurred in 7 (9.6%) HCCs and 2 (7.4%) hepatoblastomas. The AXIN1 mutations included 7 missense mutations, a 1-bp deletion, and a 12-bp insertion. The predominance of missense mutations found in the AXIN1 gene is different from the small deletions or nonsense mutations described previously. Loss of heterozygosity at the AXIN1 locus was present in 4 of 5 informative HCCs with AXIN1 mutations, suggesting a tumor suppressor function for AXIN1. AXIN2 mutations were found in 2 (2.7%) HCCs and in no hepatoblastomas. Two HCCs had both AXIN1 and beta-catenin mutations, and 1 HCC had both AXIN2 and beta-catenin mutations. About half of the HCCs with AXIN1 or AXIN2 mutations showed beta-catenin accumulation in the nucleus, cytoplasm, or membrane. Overall, the data indicated that besides the approximately 20% of HCCs and 80% of hepatoblastomas with beta-catenin mutations contributing to hepatocarcinogenesis, AXIN1 and AXIN2 mutations appear to be important in an additional 10% of HCCs and hepatoblastomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12101426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Lee, J. W., Soung, Y. H., Kim, S. Y., Lee, H. W., Park, W. S., Nam, S. W., Kim, S. H., Lee, J. Y., Yoo, N. J., Lee, S. H. <strong>PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas.</strong> Oncogene 24: 1477-1480, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15608678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15608678</a>] [<a href="https://doi.org/10.1038/sj.onc.1208304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15608678">Lee et al. (2005)</a> detected somatic mutations in the PIK3CA gene (see, e.g., <a href="/entry/171834#0007">171834.0007</a>; <a href="/entry/171834#0008">171834.0008</a>) in 26 (35.6%) of 73 hepatocellular carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15608678" 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="Li, M., Zhao, H., Zhang, X., Wood, L. D., Anders, R. A., Choti, M. A., Pawlik, T. M., Daniel, H. D., Kannangai, R., Offerhaus, G. J. A., Velculescu, V. E., Wang, L., Zhou, S., Vogelstein, B., Hruban, R. H., Papadopoulos, N., Cai. J., Torbenson, M. S., Kinzler, K. W. <strong>Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma.</strong> Nature Genet. 43: 828-829, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21822264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21822264</a>] [<a href="https://doi.org/10.1038/ng.903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21822264">Li et al. (2011)</a> performed exome sequencing of 10 HCV-associated HCCs and matched normal tissue from 10 patients and a subsequent evaluation of additional affected individuals, and discovered novel inactivating mutations of ARID2 (<a href="/entry/609539">609539</a>) in 4 major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC, and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivating mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21822264" 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="Huang, J., Deng, Q., Wang, Q., Li, K.-Y., Dai, J.-H., Li, N., Zhu, Z.-D., Zhou, B., Liu, X.-Y., Liu, R.-F., Fei, Q.-L., Chen, H., Cai, B., Zhou, B., Xiao, H.-S,., Qin, L.-X., Han, Z.-G. <strong>Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma.</strong> Nature Genet. 44: 1117-1121, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22922871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22922871</a>] [<a href="https://doi.org/10.1038/ng.2391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22922871">Huang et al. (2012)</a> used exome sequencing to identify somatic mutations in 10 hepatitis B virus-positive individuals with hepatocellular carcinoma with portal vein tumor thromboses (PVTTs), intrahepatic metastases. Both C:G-A:T and T:A-A:T transversions were frequently found among the 331 non-silent mutations. Notably, ARID1A (<a href="/entry/603024">603024</a>), which encodes a component of the SWI/SNF chromatin remodeling complex, was mutated in 14 of 110 (13%) HBV-associated HCC specimens. <a href="#15" class="mim-tip-reference" title="Huang, J., Deng, Q., Wang, Q., Li, K.-Y., Dai, J.-H., Li, N., Zhu, Z.-D., Zhou, B., Liu, X.-Y., Liu, R.-F., Fei, Q.-L., Chen, H., Cai, B., Zhou, B., Xiao, H.-S,., Qin, L.-X., Han, Z.-G. <strong>Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma.</strong> Nature Genet. 44: 1117-1121, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22922871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22922871</a>] [<a href="https://doi.org/10.1038/ng.2391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22922871">Huang et al. (2012)</a> used RNA interference to assess the roles of 91 of the confirmed mutated genes in cellular survival. The results suggested that 7 of these genes, including VCAM1 (<a href="/entry/192225">192225</a>) and CDK14 (<a href="/entry/610679">610679</a>), may confer growth and infiltration capacity to HCC cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22922871" 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>Gene Expression Studies</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Agarwal, V. R., Takayama, K., Van Wyk, J. J., Sasano, H., Simpson, E. R., Bulun, S. E. <strong>Molecular basis of severe gynecomastia associated with aromatase expression in a fibrolamellar hepatocellular carcinoma.</strong> J. Clin. Endocr. Metab. 83: 1797-1800, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9589695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9589695</a>] [<a href="https://doi.org/10.1210/jcem.83.5.4773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9589695">Agarwal et al. (1998)</a> reported a case of severe gynecomastia in a 17.5-year-old boy due to high levels of aromatase (CYP19A1; <a href="/entry/107910">107910</a>) expression in a large fibrolamellar hepatocellular carcinoma, which caused extremely elevated serum levels of estrone (1200 pg/mL) and estradiol-17 (312 pg/mL) that suppressed follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (1.3 and 2.8 IU/L, respectively) and consequently testosterone (1.53 ng/mL). After removal of the 1.5-kg tumor, gynecomastia partially regressed, and normal hormone levels were restored. By immunohistochemistry, diffuse intracytoplasmic aromatase expression was detected in the liver cancer cells. Northern blot analysis showed P450 aromatase transcripts in total RNA from the hepatocellular cancer but not in the adjacent liver nor in disease-free adult liver samples. Promoters I.3 and II were used for P450 aromatase transcription in the cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9589695" 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="#31" class="mim-tip-reference" title="Schwienbacher, C., Gramantieri, L., Scelfo, R., Veronese, A., Calin, G. A., Bolondi, L., Croce, C. M., Barbanti-Brodano, G., Negrini, M. <strong>Gain of imprinting at chromosome 11p15: a pathogenetic mechanism identified in human hepatocarcinomas.</strong> Proc. Nat. Acad. Sci. 97: 5445-5449, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10779553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10779553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10779553[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.090087497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10779553">Schwienbacher et al. (2000)</a> analyzed DNA and RNA from 52 human hepatocarcinoma samples and found abnormal imprinting of genes located at 11p15 in 51% of 37 informative samples. The most frequently detected abnormality was gain of imprinting, which led to loss of expression of genes present on the maternal chromosome. As compared with matched normal liver tissue, hepatocellular carcinoma showed extinction or significant reduction of expression of one of the alleles of the CDKN1C (<a href="/entry/600856">600856</a>), SLC22A1L (<a href="/entry/602631">602631</a>), and IGF2 (<a href="/entry/147470">147470</a>) genes. Loss of maternal-specific methylation of the KvDMR1 gene (<a href="/entry/607542">607542</a>) in hepatocarcinoma correlated with abnormal expression of CDKN1C and IGF2, suggesting a function for KvDMR1 as a long-range imprinting center active in adult tissues. These results pointed to the role of epigenetic mechanisms leading to loss of expression of imprinted genes at 11p15 in human tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10779553" 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="Ye, Q.-H., Qin, L.-X., Forgues, M., He, P., Kim, J. W., Peng, A. C., Simon, R., Li, Y., Robles, A. I., Chen, Y., Ma, Z.-C., Wu, Z.-Q., Ye, S.-L., Liu, Y.-K., Tang, Z.-Y., Wang, X. W. <strong>Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning.</strong> Nature Med. 9: 416-423, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640447</a>] [<a href="https://doi.org/10.1038/nm843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640447">Ye et al. (2003)</a> analyzed the expression profiles of hepatocellular carcinoma samples without or with intrahepatic metastases. Using a supervised machine-learning algorithm, they generated a molecular signature that can classify metastatic HCC patients and identified genes that were relevant to metastasis and patient survival (which is related particularly to intrahepatic metastases). They found that the gene expression signature of primary HCCs with accompanying metastasis was very similar to that of their corresponding metastases, implying that genes favoring metastasis progression were initiated in the primary tumors. Osteopontin (OPN; <a href="/entry/166490">166490</a>), which was identified as a lead gene in the signature, was overexpressed in metastatic HCC; an osteopontin-specific antibody effectively blocked HCC in vitro and inhibited pulmonary metastasis of HCC cells in nude mice. Thus, osteopontin acts as both a diagnostic marker and a potential therapeutic target for metastatic HCC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640447" 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="Tanabe, K. K., Lemoine, A., Finkelstein, D. M., Kawasaki, H., Fujii, T., Chung, R. T., Lauwers, G. Y., Kulu, Y., Muzikansky, A., Kuruppu, D., Lanuti, M., Goodwin, J. M., Azoulay, D., Fuchs, B. C. <strong>Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis.</strong> JAMA 299: 53-60, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18167406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18167406</a>] [<a href="https://doi.org/10.1001/jama.2007.65" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18167406">Tanabe et al. (2008)</a> reported an association between a 61A-G SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4444903;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4444903</a>) in the EGF gene (<a href="/entry/131530">131530</a>) and the development of hepatocellular carcinoma in patients with cirrhosis. Secretion of EGF was 2.3-fold higher in G/G hepatocellular carcinoma cell lines compared to A/A cell lines, and mRNA transcripts with the G allele showed a longer half-life and increased stability. Among 207 patients with cirrhosis, liver EGF levels were 2.4-fold higher in G/G patients compared to A/A patients. Fifty-nine of the 207 patients with cirrhosis also had hepatocellular carcinoma, and there was a 4-fold increased odds of hepatocellular carcinoma in G/G patients compared with A/A patients. The association was validated in a second cohort of 121 patients with alcoholic cirrhosis and hepatocellular carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18167406" 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="Ji, J., Shi, J., Budhu, A., Yu, Z., Forgues, M., Roessler, S., Ambs, S., Chen, Y., Meltzer, P. S., Croce, C. M., Qin, L.-X., Man, K., Lo, C.-M., Lee, J., Ng, I. O. L., Fan, J., Tang, Z.-Y., Sun, H.-C., Wang, X. W. <strong>MicroRNA expression, survival, and response to interferon in liver cancer.</strong> New Eng. J. Med. 361: 1437-1447, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19812400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19812400</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19812400[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa0901282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19812400">Ji et al. (2009)</a> analyzed hepatocellular carcinoma tissue derived from 455 patients from Shanghai and Hong Kong. Most of the patients were men (85.1%), were long-term carriers of the hepatitis B virus (HBV) (90.5%), had cirrhosis (88.0%), and an elevated serum level of alpha-fetoprotein (62.2%). The expression of MIRN26A1 (<a href="/entry/612151">612151</a>) and MIRN26B (<a href="/entry/612152">612152</a>) was decreased in tumor tissue compared to non-tumor tissue. Sex stratification showed that women had significantly higher expression of the MIRN26 genes in non-tumor liver tissue compared to men. Gene expression profiling using microarray showed distinct genetic patterns between tumors with low and high MIRN26 expression. The findings were consistent with the MIRN26 genes acting as tumor suppressors. Patients whose tumors showed low MIRN26 expression had shorter overall survival, but better response to interferon therapy compared to patients with higher expression of these MIRNs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19812400" 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="#44" class="mim-tip-reference" title="Yong, K. J., Gao, C., Lim, J. S. J., Yan, B., Yang, H., Dimitrov, T., Kawasaki, A., Ong, C. W., Wong, K.-F., Lee, S., Ravikumar, S., Srivastava, S., Tian, X., Poon, R. T., Fan, S. T., Luk, J. M., Dan, Y. Y., Salto-Tellez, M., Chai, L., Tenen, D. G. <strong>Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.</strong> New Eng. J. Med. 368: 2266-2276, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23758232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23758232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23758232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1300297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23758232">Yong et al. (2013)</a> screened specimens obtained from 179 patients with hepatocellular carcinoma from Singapore for the expression of SALL4 (<a href="/entry/607343">607343</a>). SALL4 is an oncofetal protein that is expressed in human fetal liver and silenced in the adult liver, but is reexpressed in a subgroup of patients that have hepatocellular carcinoma with unfavorable prognosis. Gene expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive hepatocellular carcinomas. <a href="#44" class="mim-tip-reference" title="Yong, K. J., Gao, C., Lim, J. S. J., Yan, B., Yang, H., Dimitrov, T., Kawasaki, A., Ong, C. W., Wong, K.-F., Lee, S., Ravikumar, S., Srivastava, S., Tian, X., Poon, R. T., Fan, S. T., Luk, J. M., Dan, Y. Y., Salto-Tellez, M., Chai, L., Tenen, D. G. <strong>Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.</strong> New Eng. J. Med. 368: 2266-2276, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23758232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23758232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23758232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1300297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23758232">Yong et al. (2013)</a> found that in a multivariate Cox regression model, SALL4 is an independent prognostic factor for overall survival (hazard ratio for death, 2.87; 95% confidence interval, 1.09 to 7.52; p = 0.03) in the Singapore cohort and an independent predictor of both overall survival (hazard ratio for death, 1.52; 95% confidence interval, 1.00-2.32; p = 0.05) and early recurrence (hazard ratio, 1.67; 95% CI, 1.11-2.51; p = 0.01) in the Hong Kong cohort. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (<a href="/entry/601728">601728</a>) and inhibited tumor formation in xenograft models in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23758232" 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 help avoid additional risks associated with tumor biopsy in patients with SALL4-negative tumors, <a href="#14" class="mim-tip-reference" title="Hopkins, L. J., Rowe, I. A. C., Houlihan, D. D. <strong>Comment on 'Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.' (Letter)</strong> New Eng. J. Med. 369: 1170 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24047069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24047069</a>] [<a href="https://doi.org/10.1056/NEJMc1308785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24047069">Hopkins et al. (2013)</a> requested that <a href="#44" class="mim-tip-reference" title="Yong, K. J., Gao, C., Lim, J. S. J., Yan, B., Yang, H., Dimitrov, T., Kawasaki, A., Ong, C. W., Wong, K.-F., Lee, S., Ravikumar, S., Srivastava, S., Tian, X., Poon, R. T., Fan, S. T., Luk, J. M., Dan, Y. Y., Salto-Tellez, M., Chai, L., Tenen, D. G. <strong>Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.</strong> New Eng. J. Med. 368: 2266-2276, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23758232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23758232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23758232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1300297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23758232">Yong et al. (2013)</a> determine the sensitivity and specificity of the serum alpha-fetoprotein level in predicting the SALL4 status of their hepatocellular carcinoma patients. <a href="#43" class="mim-tip-reference" title="Yong, K. J., Chai, L., Tenen, D. G. <strong>Reply to comments on 'Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.' (Letter)</strong> New Eng. J. Med. 369: 1172-1173, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24047073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24047073</a>] [<a href="https://doi.org/10.1056/NEJMc1309091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24047073">Yong et al. (2013)</a> replied that in the Hong Kong cohort of patients with hepatocellular carcinoma they observed a significant correlation between SALL4 mRNA expression and the serum alpha-fetoprotein level (p less than 0.001). The sensitivity and specificity of serum alpha-fetoprotein levels in predicting SALL4 expression in this cohort of 228 patients were calculated to be 66.7% and 68.4%, respectively. The data suggested that with a cutoff value of 100 ng per milliliter, a serum alpha-fetoprotein level of 100 ng per milliliter or more can identify 66.7% of patients with SALL4 mRNA expression. However, 31.6% of patients without SALL4 expression would be falsely identified as being positive for SALL4 expression. <a href="#43" class="mim-tip-reference" title="Yong, K. J., Chai, L., Tenen, D. G. <strong>Reply to comments on 'Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.' (Letter)</strong> New Eng. J. Med. 369: 1172-1173, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24047073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24047073</a>] [<a href="https://doi.org/10.1056/NEJMc1309091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24047073">Yong et al. (2013)</a> suggested that, to assess SALL4 expression without the need for patient biopsy specimens, a noninvasive assay to test serum SALL4 expression be developed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24047073+23758232+24047069" 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="#36" class="mim-tip-reference" title="Suzuki, E., Chiba, T., Yokosuka, O. <strong>Comment on 'Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.' (Letter)</strong> New Eng. J. Med. 369: 1170-1171, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24047070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24047070</a>] [<a href="https://doi.org/10.1056/NEJMc1308785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24047070">Suzuki et al. (2013)</a> asked of <a href="#44" class="mim-tip-reference" title="Yong, K. J., Gao, C., Lim, J. S. J., Yan, B., Yang, H., Dimitrov, T., Kawasaki, A., Ong, C. W., Wong, K.-F., Lee, S., Ravikumar, S., Srivastava, S., Tian, X., Poon, R. T., Fan, S. T., Luk, J. M., Dan, Y. Y., Salto-Tellez, M., Chai, L., Tenen, D. G. <strong>Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.</strong> New Eng. J. Med. 368: 2266-2276, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23758232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23758232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23758232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1300297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23758232">Yong et al. (2013)</a> whether the unfavorable clinical outcome in high-SALL4 hepatocellular carcinoma is attributable to features of cholangiocarcinoma. <a href="#25" class="mim-tip-reference" title="Masuda, S., Suzuki, K., Izpisua Belmonte, J. C. <strong>Comment on 'Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.' (Letter)</strong> New Eng. J. Med. 369: 1171 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24047071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24047071</a>] [<a href="https://doi.org/10.1056/NEJMc1308785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24047071">Masuda et al. (2013)</a> inquired whether reprogramming factors such as KLF5 or TBX3 could be involved in the pathogenesis of SALL4-related hepatocellular carcinoma, and if reexpression of SALL4 through hepatitis B infection has a role in upregulation of SALL4. <a href="#43" class="mim-tip-reference" title="Yong, K. J., Chai, L., Tenen, D. G. <strong>Reply to comments on 'Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.' (Letter)</strong> New Eng. J. Med. 369: 1172-1173, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24047073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24047073</a>] [<a href="https://doi.org/10.1056/NEJMc1309091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24047073">Yong et al. (2013)</a> replied that more studies would be necessary to address these queries. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24047071+23758232+24047073+24047070" 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>Hepatitis B Infection</em></strong></p><p>
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Integration of HBV into cellular DNA occurs during long-term persistent infection in man. Hepatocellular carcinomas isolated from carriers of virus often contain clonally propagated viral DNA. <a href="#33" class="mim-tip-reference" title="Shen, F.-M., Lee, M. K., Gong, H.-M., Cai, X.-Q., King, M.-C. <strong>Complex segregation analysis of primary hepatocellular carcinoma in Chinese families: interaction of inherited susceptibility and hepatitis B viral infection.</strong> Am. J. Hum. Genet. 49: 88-93, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1648308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1648308</a>]" pmid="1648308">Shen et al. (1991)</a> presented evidence for the interaction of inherited susceptibility and hepatitis B viral infection in cases of primary hepatocellular carcinoma in eastern China. Complex segregation analysis of 490 extended families supported the existence of a recessive allele with population frequency approximately 0.25, which results in a lifetime risk of HCC in the presence of both HBV infection and genetic susceptibility, of 0.84 for males and 0.46 for females. The model further predicted that, in the absence of genetic susceptibility, lifetime risk of HCC is 0.09 for HBV-infected males and 0.01 for HBV-infected females and that regardless of genotype the risk is virtually zero for uninfected persons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1648308" 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 finding of small deletions in retinoblastoma and Wilms tumor prompted <a href="#30" class="mim-tip-reference" title="Rogler, C. E., Sherman, M., Su, C. Y., Shafritz, D. A., Summers, J., Shows, T. B., Henderson, A., Kew, M. <strong>Deletion in chromosome 11p associated with a hepatitis B integration site in hepatocellular carcinoma.</strong> Science 230: 319-322, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2996131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2996131</a>] [<a href="https://doi.org/10.1126/science.2996131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2996131">Rogler et al. (1985)</a> to look for the same in association with HBV integration in hepatocellular carcinoma. They demonstrated a deletion of at least 13.5 kb of cellular sequences in a liver cancer. The HBV integration and the deletion occurred on the short arm of chromosome 11 at location 11p14-p13. The deleted sequences were lost in tumor cells leaving only a single copy. Clones of the DNA flanking the deleted segment were used for the mapping of the deletion in somatic cell hybrids and by in situ hybridization. Cellular sequences homologous to the deleted region were cloned and used to exclude the possibility that this DNA had been moved to other positions in the genome. <a href="#8" class="mim-tip-reference" title="Fisher, J. H., Scoggin, C. H., Rogler, C. E. <strong>Sequences which flank an 11p deletion observed in an hepatocellular carcinoma map to 11p13.</strong> Hum. Genet. 75: 66-69, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3026949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3026949</a>] [<a href="https://doi.org/10.1007/BF00273842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3026949">Fisher et al. (1987)</a> extended the observations of <a href="#30" class="mim-tip-reference" title="Rogler, C. E., Sherman, M., Su, C. Y., Shafritz, D. A., Summers, J., Shows, T. B., Henderson, A., Kew, M. <strong>Deletion in chromosome 11p associated with a hepatitis B integration site in hepatocellular carcinoma.</strong> Science 230: 319-322, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2996131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2996131</a>] [<a href="https://doi.org/10.1126/science.2996131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2996131">Rogler et al. (1985)</a>. Using somatic cell hybrids that contained defined 11p deletions, 2 cloned DNA sequences that flank the deletion generated by a hepatocellular carcinoma (as a consequence of hepatitis B virus integration) were mapped to 11p13. Wilms tumor (<a href="/entry/194070">194070</a>) and the tumors of Beckwith-Wiedemann syndrome (<a href="/entry/130650">130650</a>) are also determined by changes on 11p. <a href="#41" class="mim-tip-reference" title="Wang, H. P., Rogler, C. E. <strong>Deletions in human chromosome arms 11p and 13q in primary hepatocellular carcinomas.</strong> Cytogenet. Cell Genet. 48: 72-78, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2904349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2904349</a>] [<a href="https://doi.org/10.1159/000132593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2904349">Wang and Rogler (1988)</a> found loss of heterozygosity in 11p and 13q. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3026949+2996131+2904349" 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>Integration of DNA from the hepatitis B virus has been shown to occur frequently in human hepatocellular carcinomas. Recombinant DNA probes have been isolated from such a tumor. These probes detected rearrangements of the corresponding DNA domain in 10% of liver tumors regardless of whether they were HBV-related or not (<a href="#29" class="mim-tip-reference" title="Pasquinelli, C., Garreau, F., Bougueleret, L., Cariani, E., Grzeschik, K. H., Thiers, V., Croissant, O., Hadchouel, M., Tiollais, P., Brechot, C. <strong>Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors.</strong> J. Virol. 62: 629-632, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2826820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2826820</a>] [<a href="https://doi.org/10.1128/JVI.62.2.629-632.1988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2826820">Pasquinelli et al., 1988</a>). Blanquet et al. (<a href="#2" class="mim-tip-reference" title="Blanquet, V., Garreau, F., Brechot, C., Turleau, C. <strong>Regional mapping by in situ hybridization of a DNA segment rearranged in human liver tumors to 4q32.1. (Abstract)</strong> Cytogenet. Cell Genet. 46: 582 only, 1987."None>1987</a>, <a href="#3" class="mim-tip-reference" title="Blanquet, V., Garreau, F., Chenivesse, X., Brechot, C., Turleau, C. <strong>Regional mapping to 4q32.1 by in situ hybridization of a DNA domain rearranged in human liver cancer.</strong> Hum. Genet. 80: 274-276, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2847975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2847975</a>] [<a href="https://doi.org/10.1007/BF01790096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2847975">1988</a>) cloned the normal allele and used it for mapping an HCC locus by somatic cell hybrid studies and by in situ hybridization. These experiments showed that the locus is located in the area 4q32.1. <a href="#4" class="mim-tip-reference" title="Buetow, K. H., Murray, J. C., Israel, J. L., London, W. T., Smith, M., Kew, M., Blanquet, V., Brechot, C., Redeker, A., Govindarajah, S. <strong>Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma.</strong> Proc. Nat. Acad. Sci. 86: 8852-8856, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2573067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2573067</a>] [<a href="https://doi.org/10.1073/pnas.86.22.8852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2573067">Buetow et al. (1989)</a> found that 7 of 11 primary liver tumors tested against a panel of RFLPs demonstrated loss of constitutional heterozygosity for markers on chromosome 4, particularly 4q. <a href="#4" class="mim-tip-reference" title="Buetow, K. H., Murray, J. C., Israel, J. L., London, W. T., Smith, M., Kew, M., Blanquet, V., Brechot, C., Redeker, A., Govindarajah, S. <strong>Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma.</strong> Proc. Nat. Acad. Sci. 86: 8852-8856, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2573067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2573067</a>] [<a href="https://doi.org/10.1073/pnas.86.22.8852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2573067">Buetow et al. (1989)</a> suggested that chronic hepatitis B virus infection and other environmental agents may operate through genetic events leading to loss of a tumor suppressor locus (anti-oncogene) on chromosome 4. The findings were thought to be consistent with those of <a href="#29" class="mim-tip-reference" title="Pasquinelli, C., Garreau, F., Bougueleret, L., Cariani, E., Grzeschik, K. H., Thiers, V., Croissant, O., Hadchouel, M., Tiollais, P., Brechot, C. <strong>Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors.</strong> J. Virol. 62: 629-632, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2826820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2826820</a>] [<a href="https://doi.org/10.1128/JVI.62.2.629-632.1988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2826820">Pasquinelli et al. (1988)</a>, which placed the critical region in the vicinity of 4q32. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2847975+2573067+2826820" 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="Smith, M., Yoshiyama, K., Kew, M. <strong>Evidence for chromosome 4q deletions in human hepatomas. (Abstract)</strong> Cytogenet. Cell Genet. 51: 1081 only, 1989."None>Smith et al. (1989)</a> gave evidence for microdeletions of chromosome 4q involving the alcohol dehydrogenase isoenzyme gene ADH3 (ADH1C; <a href="/entry/103730">103730</a>) and hepatomas from 3 of 5 individuals heterozygous for an XbaI RFLP detectable by the ADH probe. Two of 7 individuals heterozygous for an epidermal growth factor RFLP had lost 1 EGF allele in their hepatoma tissue.</p><p><a href="#11" class="mim-tip-reference" title="Henderson, A. S., Ripley, S., Hino, O., Rogler, C. E. <strong>Identification of a chromosomal aberration associated with a hepatitis B DNA integration site in human cells.</strong> Cancer Genet. Cytogenet. 30: 269-275, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2830013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2830013</a>] [<a href="https://doi.org/10.1016/0165-4608(88)90194-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2830013">Henderson et al. (1988)</a> demonstrated that the integration of HBV DNA can result in, or be accompanied by, interchromosomal exchange of genomic material containing the integrated DNA. Using in situ hybridization, they found that unique cellular DNA to the left of an HBV DNA integration site, cloned from a primary tumor, mapped to chromosome 18q (18q11.1-q11.2); right-hand flanking DNA mapped to chromosome 17 (17q22-q25). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2830013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a hepatoma specimen from Shanghai, <a href="#48" class="mim-tip-reference" title="Zhou, Y.-Z., Slagle, B. L., Donehower, L. A., vanTuinen, P., Ledbetter, D. H., Butel, J. S. <strong>Structural analysis of a hepatitis B virus genome integrated into chromosome 17p of a human hepatocellular carcinoma.</strong> J. Virol. 62: 4224-4231, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2845134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2845134</a>] [<a href="https://doi.org/10.1128/JVI.62.11.4224-4231.1988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2845134">Zhou et al. (1988)</a> identified integration of hepatitis B virus into 17p12-p11.2, which is near the human protooncogene p53 (<a href="/entry/191170">191170</a>). Furthermore, the sequence of flanking cellular DNA showed highly significant homology with a conserved region of a number of functional mammalian DNAs, including the human autonomously replicated sequence-1 (ARS1; <a href="/entry/109110">109110</a>). ARS1 is a sequence of human DNA that allows replication of Saccharomyces cerevisiae integrative plasmids as autonomously replicating elements in S. cerevisiae cells. Since integration of viral DNA is not a required step in the replicative cycle of the hepatitis virus, the presence of integrated HBV sequences in many human hepatocellular carcinomas suggests a causal relationship. Since any 1 of several integration sites may lead to the same result, the crucial cellular targets involved in triggering liver cell malignant transformation may differ from tumor to tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2845134" 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>Primary hepatocellular carcinoma occurs at high frequencies in east Asia and sub-Saharan Africa. In these areas of the world, chronic infection with the hepatitis B virus is the best documented risk factor; however, only 20 to 25% of HBV carriers develop HCC. Exposure to the fungal toxin aflatoxin B1 (AFB1) has been suggested to increase HCC risk, in part because in vitro experiments demonstrated that AFB1 mutagenic metabolites bind to DNA and are capable of inducing G-to-T transversions. In certain areas of the HCC endemic regions, a mutation hotspot has been reported in the p53 tumor suppressor gene (TP53; <a href="/entry/191170">191170</a>): an AGG-to-AGT transversion (arginine to serine) of codon 249 in exon 7 (<a href="/entry/191170#0006">191170.0006</a>). Microsomal epoxide hydrolase (EPHX; <a href="/entry/132810">132810</a>) and glutathione-S-transferase M1 (GSTM1; <a href="/entry/138350">138350</a>) are both involved in AFB1 detoxification in hepatocytes. Polymorphism of both genes has been identified. In Ghana and China, <a href="#26" class="mim-tip-reference" title="McGlynn, K. A., Rosvold, E. A., Lustbader, E. D., Hu, Y., Clapper, M. L., Zhou, T., Wild, C. P., Xia, X.-L., Baffoe-Bonnie, A., Ofori-Adjei, D., Chen, G.-C., London, W. T., Shen, F.-M., Buetow, K. H. <strong>Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.</strong> Proc. Nat. Acad. Sci. 92: 2384-2387, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7892276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7892276</a>] [<a href="https://doi.org/10.1073/pnas.92.6.2384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7892276">McGlynn et al. (1995)</a> conducted studies to determine whether mutant alleles at one or both of these loci are associated with increased levels of serum AFB1-albumin adducts, with HCC, and with mutations at codon 249 of p53. In a cross-sectional study, they found that mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1 albumin adducts. Additionally, in a case-control study, mutant alleles of EPHX were significantly overrepresented in persons with HCC. The relationship of EPHX to HCC varied by hepatitis B surface antigen status, indicating that a synergistic effect may exist. Mutations at codon 249 of p53 were observed only among HCC patients with one or both high-risk genotypes. These findings by <a href="#26" class="mim-tip-reference" title="McGlynn, K. A., Rosvold, E. A., Lustbader, E. D., Hu, Y., Clapper, M. L., Zhou, T., Wild, C. P., Xia, X.-L., Baffoe-Bonnie, A., Ofori-Adjei, D., Chen, G.-C., London, W. T., Shen, F.-M., Buetow, K. H. <strong>Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.</strong> Proc. Nat. Acad. Sci. 92: 2384-2387, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7892276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7892276</a>] [<a href="https://doi.org/10.1073/pnas.92.6.2384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7892276">McGlynn et al. (1995)</a> supported the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicated that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7892276" 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="#6" class="mim-tip-reference" title="Chiu, C.-M., Yeh, S.-H., Chen, P.-J., Kuo, T.-J., Chang, C.-J., Chen, P.-J., Yang, W.-J., Chen, D.-S. <strong>Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level.</strong> Proc. Nat. Acad. Sci. 104: 2571-2578, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17259306[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0609498104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259306">Chiu et al. (2007)</a> examined the roles of androgen receptor (AR; <a href="/entry/313700">313700</a>) and the HBV nonstructural protein HBx in hepatocellular carcinoma, a disease that predominantly affects males. HBx increased the anchorage-independent colony formation potency of AR in a nontransformed mouse hepatocyte cell line. AR-mediated transcriptional activity was enhanced by HBx in an androgen concentration-dependent manner. Mutation analysis showed that HBx-enhanced AR gene transcriptional activity required intact HBx and the hinge region of AR. Immunoprecipitation and cell fractionation analyses revealed that HBx-AR interactions occurred mainly in the cytosol. HBx-enhanced AR activation involved SRC (<a href="/entry/190090">190090</a>) activity. <a href="#6" class="mim-tip-reference" title="Chiu, C.-M., Yeh, S.-H., Chen, P.-J., Kuo, T.-J., Chang, C.-J., Chen, P.-J., Yang, W.-J., Chen, D.-S. <strong>Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level.</strong> Proc. Nat. Acad. Sci. 104: 2571-2578, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17259306[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0609498104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259306">Chiu et al. (2007)</a> concluded that HBx is a noncellular positive coregulator of AR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17259306" 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>Glycogen Storage Disease Type Ia</em></strong></p><p>
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Hepatocellular adenoma (HCA) is a frequent long-term complication of glycogen storage disease type I (GSD I; <a href="/entry/232200">232200</a>), and malignant transformation to hepatocellular carcinoma (HCC) occurs in some cases. <a href="#20" class="mim-tip-reference" title="Kishnani, P. S., Chuang, T.-P., Bali, D., Koeberl, D., Austin, S., Weinstein, D. A., Murphy, E., Chen, Y.-T., Boyette, K., Liu, C.-H., Chen, Y.-T., Li, L.-H. <strong>Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease.</strong> Hum. Molec. Genet. 18: 4781-4790, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19762333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19762333</a>] [<a href="https://doi.org/10.1093/hmg/ddp441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19762333">Kishnani et al. (2009)</a> performed genomewide SNP analysis and mutation detection of target genes in 10 GSD Ia-associated HCA and 7 general population HCA cases. Chromosomal aberrations were detected in 60% of the GSD Ia HCA and 57% of general population HCA. Coincident gain of chromosome 6p and loss of 6q were seen only in GSD Ia HCA (3 cases) with 1 additional GSD I patient showing submicroscopic 6q14.1 deletion. The sizes of GSD Ia adenomas with chromosome 6 aberrations were larger than the sizes of adenomas without the changes (P = 0.012). Expression of IGF2R (FCGR2A; <a href="/entry/146790">146790</a>) and LATS1 (<a href="/entry/603473">603473</a>) candidate tumor suppressor genes at 6q was reduced in more than 50% of 7 GSD Ia HCA examined. None of the GSD Ia HCA had biallelic mutations in the HNF1A (<a href="/entry/142410">142410</a>) gene. The authors suggested that chromosome 6 alterations could be an early event in the liver tumorigenesis in GSD I, and possibly in general population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19762333" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations with HCC in Chronic HBV Carriers Pending Confirmation</em></strong></p><p>
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By means of genetic association analysis, <a href="#34" class="mim-tip-reference" title="Shin, H. D., Park, B. L., Kim, L. H., Jung, J. H., Kim, J. Y., Yoon, J. H., Kim, Y. J., Lee, H.-S. <strong>Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma.</strong> Hum. Molec. Genet. 12: 901-906, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668613</a>] [<a href="https://doi.org/10.1093/hmg/ddg104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668613">Shin et al. (2003)</a> showed that the interleukin-10 (IL10; <a href="/entry/124092">124092</a>) haplotype IL10-ht2 was strongly associated with hepatocellular carcinoma in a well-characterized HBV cohort. The frequency of susceptible IL10-ht2 was much higher in HCC patients and significantly increased in order of susceptibility to HBV progression from chronic hepatitis to liver cirrhosis and HCC among hepatitis B patients. In addition, survival analysis showed that the onset age of HCC was also accelerated among chronic hepatitis B patients who were carrying IL10-ht2. <a href="#34" class="mim-tip-reference" title="Shin, H. D., Park, B. L., Kim, L. H., Jung, J. H., Kim, J. Y., Yoon, J. H., Kim, Y. J., Lee, H.-S. <strong>Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma.</strong> Hum. Molec. Genet. 12: 901-906, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668613</a>] [<a href="https://doi.org/10.1093/hmg/ddg104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668613">Shin et al. (2003)</a> suggested that increased IL10 production mediated by IL10-ht2 accelerates progression of chronic HBV infection, especially to HCC development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a genomewide association study of 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry, <a href="#47" class="mim-tip-reference" title="Zhang, H., Zhai, Y., Hu, Z., Wu, C., Qian, J., Jia, W., Ma, F., Huang, W., Yu, L., Yue, W., Wang, Z., Li, P., and 20 others. <strong>Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers.</strong> Nature Genet. 42: 755-758, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20676096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20676096</a>] [<a href="https://doi.org/10.1038/ng.638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20676096">Zhang et al. (2010)</a> found an association between HBV-related HCC and a SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17401966;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17401966</a>) in an intron of the KIF1B gene (<a href="/entry/605995">605995</a>) on chromosome 1p36.22. The association was confirmed in 5 additional independent Chinese samples, consisting of 1,962 individuals with HCC, 1,430 control subjects, and 159 family trios. Across all 6 studies, the combined p value for the protective G allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17401966;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17401966</a> was 1.7 x 10(-18), with an odds ratio of 0.61. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20676096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations with HCC in Chronic HCV Carriers Pending Confirmation</em></strong></p><p>
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<a href="#21" class="mim-tip-reference" title="Kumar, V., Kato, N., Urabe, Y., Takahashi, A., Muroyama, R., Hosono, N., Otsuka, M., Tateishi, R., Omata, M. Nakagawa, H., Koike, K., Kamatani, N., Kubo, M., Nakamura, Y., Matsuda, K. <strong>Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma.</strong> Nature Genet. 43: 455-458, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21499248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21499248</a>] [<a href="https://doi.org/10.1038/ng.809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21499248">Kumar et al. (2011)</a> conducted a genomewide association study using 432,703 autosomal SNPs in 721 individuals with HCV-induced HCC and 2,890 HCV-negative controls of Japanese origin. Eight SNPs that showed possible association in the genomewide association study were further genotyped in 673 cases and 2,596 controls. <a href="#21" class="mim-tip-reference" title="Kumar, V., Kato, N., Urabe, Y., Takahashi, A., Muroyama, R., Hosono, N., Otsuka, M., Tateishi, R., Omata, M. Nakagawa, H., Koike, K., Kamatani, N., Kubo, M., Nakamura, Y., Matsuda, K. <strong>Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma.</strong> Nature Genet. 43: 455-458, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21499248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21499248</a>] [<a href="https://doi.org/10.1038/ng.809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21499248">Kumar et al. (2011)</a> found a previously unidentified locus in the 5-prime flanking region of MICA (<a href="/entry/600169">600169</a>) on 6p21.33 (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2596542;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2596542</a>, combined p = 4.21 x 10(-13), odds ratio = 1.39) to be strongly associated with HCV-induced HCC. Subsequent analyses using individuals with chronic hepatitis C (CHC) indicated that this SNP is not associated with CHC susceptibility but is significantly associated with progression from CHC to HCC (p = 3.13 x 10(-8)). <a href="#21" class="mim-tip-reference" title="Kumar, V., Kato, N., Urabe, Y., Takahashi, A., Muroyama, R., Hosono, N., Otsuka, M., Tateishi, R., Omata, M. Nakagawa, H., Koike, K., Kamatani, N., Kubo, M., Nakamura, Y., Matsuda, K. <strong>Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma.</strong> Nature Genet. 43: 455-458, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21499248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21499248</a>] [<a href="https://doi.org/10.1038/ng.809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21499248">Kumar et al. (2011)</a> also found that the risk allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2596542;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2596542</a> was associated with lower soluble MICA protein levels in individuals with HCV-induced HCC (p = 1.38 x 10(-13)). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21499248" 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="#45" class="mim-tip-reference" title="Yoo, B. K., Emdad, L., Su, Z., Villanueva, A., Chiang, D. Y., Mukhopadhyay, N. D., Mills, A. S., Waxman, S., Fisher, R. A., Llovet, J. M., Fisher, P. B., Sarkar, D. <strong>Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression.</strong> J. Clin. Invest. 119: 465-477, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19221438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19221438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19221438[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI36460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19221438">Yoo et al. (2009)</a> found that expression of AEG1 (MTDH; <a href="/entry/610323">610323</a>) was significantly elevated in hepatocellular carcinomas compared with normal human hepatocytes. Stable expression of AEG1 increased the aggressiveness of nontumorigenic human HCC cells, and inhibition of AEG1 abrogated tumorigenesis by aggressive HCC cells in a xenograft model of nude mice. In humans, AEG1 overexpression was associated with elevated copy number. Microarray analysis revealed that AEG1 modulated the expression of genes associated with invasion, metastasis, chemoresistance, angiogenesis, and senescence. AEG1 specifically activated Wnt (see <a href="/entry/164820">164820</a>)/beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>) signaling, resulting in upregulation of LEF1 (<a href="/entry/153245">153245</a>), the ultimate executor of the Wnt signaling pathway. AEG1 also activated the NF-kappa-B (see <a href="/entry/164011">164011</a>) pathway, which may play a role in the chronic inflammatory changes preceding HCC development. <a href="#45" class="mim-tip-reference" title="Yoo, B. K., Emdad, L., Su, Z., Villanueva, A., Chiang, D. Y., Mukhopadhyay, N. D., Mills, A. S., Waxman, S., Fisher, R. A., Llovet, J. M., Fisher, P. B., Sarkar, D. <strong>Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression.</strong> J. Clin. Invest. 119: 465-477, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19221438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19221438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19221438[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI36460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19221438">Yoo et al. (2009)</a> concluded that AEG1 plays a central role in HCC pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19221438" 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 cDNA microarray, Western blot analysis, and luciferase constructs, <a href="#46" class="mim-tip-reference" title="Yoo, B. K., Gredler, R., Vozhilla, N., Su, Z., Chen, D., Forcier, T., Shah, K., Saxena, U., Hansen, U., Fisher, P. B., Sarkar, D. <strong>Identification of genes conferring resistance to 5-fluorouracil.</strong> Proc. Nat. Acad. Sci. 106: 12938-12943, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19622726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19622726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19622726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0901451106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19622726">Yoo et al. (2009)</a> found significant upregulation of the transcription factor LSF (TFCP2; <a href="/entry/189889">189889</a>) and increased LSF transcriptional activity in the nuclei of hepatocellular carcinoma cells expressing AEG1 compared to those without AEG1 expression. The increase in LSF activity correlated with significant increases in the downstream targets thymidylate synthetase (TYMS; <a href="/entry/188350">188350</a>) during the growth cycle and dihydropyrimidine dehydrogenase (DPYD; <a href="/entry/612779">612779</a>). The AEG1-transfected HCC cells showed more resistance to 5-fluorouracil (5-FU) treatment compared to those without AEG1 expression, which could be explained by the upregulation of both TYMS and DPYD. Studies with siRNA targeting AEG1, LSF, or DPYD abrogated the 5-FU resistance. In nude xenograft mice transfected with an HCC cell line that expressed AEG1 and showed resistance to 5-FU, inhibition of AEG1 resulted in significant inhibition in tumor growth, and a combination of 5-FU and AEG1 inhibition resulted in an additive effect on tumor growth inhibition. The findings demonstrated that AEG1 confers resistance to 5-FU by inducing the expression of LSF and DPYD, and pointed to a central role of AEG1 in HCC development and progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19622726" 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 S-III subtype of hepatitis B-related hepatocellular carcinoma is characterized by disrupted cholesterol homeostasis, and is associated with the lowest overall rate of survival among the 3 subtypes characterized by <a href="#18" class="mim-tip-reference" title="Jiang, Y., Sun, A., Zhao, Y., Ying, W., Sun, H., Yang, X., Xing, B., Sun, W., Ren, L., Hu, B., Li, C., Zhang, L., and 27 others. <strong>Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma.</strong> Nature 567: 257-261, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30814741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30814741</a>] [<a href="https://doi.org/10.1038/s41586-019-0987-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30814741">Jiang et al. (2019)</a> and the greatest risk of a poor prognosis after first-line surgery. <a href="#18" class="mim-tip-reference" title="Jiang, Y., Sun, A., Zhao, Y., Ying, W., Sun, H., Yang, X., Xing, B., Sun, W., Ren, L., Hu, B., Li, C., Zhang, L., and 27 others. <strong>Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma.</strong> Nature 567: 257-261, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30814741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30814741</a>] [<a href="https://doi.org/10.1038/s41586-019-0987-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30814741">Jiang et al. (2019)</a> found that knockdown of sterol O-acyltransferase-1 (SOAT1; <a href="/entry/102642">102642</a>), high expression of which is a signature specific to the S-III subtype, altered the distribution of cellular cholesterol, and effectively suppressed the proliferation and migration of hepatocellular carcinoma. On the basis of a patient-derived tumor xenograft mouse model of hepatocellular carcinoma, <a href="#18" class="mim-tip-reference" title="Jiang, Y., Sun, A., Zhao, Y., Ying, W., Sun, H., Yang, X., Xing, B., Sun, W., Ren, L., Hu, B., Li, C., Zhang, L., and 27 others. <strong>Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma.</strong> Nature 567: 257-261, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30814741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30814741</a>] [<a href="https://doi.org/10.1038/s41586-019-0987-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30814741">Jiang et al. (2019)</a> found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumors that had high levels of SOAT1 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30814741" 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>HCC and intrahepatic cholangiocarcinoma (ICC; <a href="/entry/615619">615619</a>) differ markedly with regards to their morphology, metastatic potential, and responses to therapy. <a href="#32" class="mim-tip-reference" title="Seehawer, M., Heinzmann, F., D'Artista, L., Harbig, J., Roux, P. F., Hoenicke, L., Dang, H., Klotz, S., Robinson, L., Dore, G., Rozenblum, N., Kang, T.-W., and 12 others. <strong>Necroptosis microenvironment directs lineage commitment in liver cancer.</strong> Nature 562: 69-75, 2018. Note: Erratum: Nature 564: E9, 2018. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30209397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30209397</a>] [<a href="https://doi.org/10.1038/s41586-018-0519-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30209397">Seehawer et al. (2018)</a> demonstrated that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 (<a href="/entry/601621">601621</a>) and Prdm5 (<a href="/entry/614161">614161</a>) as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. <a href="#32" class="mim-tip-reference" title="Seehawer, M., Heinzmann, F., D'Artista, L., Harbig, J., Roux, P. F., Hoenicke, L., Dang, H., Klotz, S., Robinson, L., Dore, G., Rozenblum, N., Kang, T.-W., and 12 others. <strong>Necroptosis microenvironment directs lineage commitment in liver cancer.</strong> Nature 562: 69-75, 2018. Note: Erratum: Nature 564: E9, 2018. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30209397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30209397</a>] [<a href="https://doi.org/10.1038/s41586-018-0519-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30209397">Seehawer et al. (2018)</a> concluded that their results provided insight into lineage commitment in liver tumorigenesis, and explained molecularly why common liver-damaging risk factors can lead to either HCC or ICC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30209397" 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>Fibrolamellar Hepatocellular Carcinoma</em></strong></p><p>
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Fibrolamellar HCC is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis. <a href="#13" class="mim-tip-reference" title="Honeyman, J. N., Simon, E. P., Robine, N., Chiaroni-Clarke, R., Darcy, D. G., Lim, I. I. P., Gleason, C. E., Murphy, J. M., Rosenberg, B. R., Teegan, L., Takacs, C. N., Botero, S., Belote, R., Germer, S., Emde, A.-K., Vacic, V., Bhanot, U., LaQuaglia, M. P., Simon, S. M. <strong>Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.</strong> Science 343: 1010-1014, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24578576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24578576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24578576[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1249484" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24578576">Honeyman et al. (2014)</a> identified a chimeric transcript that is expressed in fibrolamellar HCC but not in adjacent normal liver and that arises as the result of an approximately 400-kb deletion on chromosome 19. The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1 (<a href="/entry/604572">604572</a>), a homolog of the molecular chaperone DNAJ, fused in-frame with PRKACA (<a href="/entry/601639">601639</a>), the catalytic domain of protein kinase A. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the fibrolamellar HCCs examined (15 of 15) suggests that this genetic alteration contributes to tumor pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24578576" 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="#12" class="mim-tip-reference" title="Hill-Baskin, A. E., Markiewski, M. M., Buchner, D. A., Shao, H., DeSantis, D., Hsaio, G., Subramaniam, S., Berger, N. A., Croniger, C., Lambris, J. D., Nadeau, J. H. <strong>Diet-induced hepatocellular carcinoma in genetically predisposed mice.</strong> Hum. Molec. Genet. 18: 2975-2988, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19454484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19454484</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19454484[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19454484">Hill-Baskin et al. (2009)</a> tested the long-term effects of high- and low-fat diets on male mice of 2 inbred strains and discovered that C57BL/6J but not A/J male mice were susceptible to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) on a high- but not low-fat diet. Susceptible mice showed morphologic characteristics of NASH (steatosis, hepatitis, fibrosis, and cirrhosis), dysplasia, and HCC. The mRNA profiles of HCCs versus tumor-free liver showed involvement of 2 signaling networks, one centered on Myc (<a href="/entry/190080">190080</a>) and the other on NFKB1 (<a href="/entry/164011">164011</a>), similar to signaling described for the 2 major classes of HCC in humans. The miRNA profiles revealed dramatically increased expression of a cluster of miRNAs on the X chromosome without amplification of the chromosomal segment. A switch from high- to low-fat diet reversed these outcomes, with switched C57BL/6J males being lean rather than obese and without evidence for NASH or HCCs at the end of the study. A similar diet modification may have important implications for prevention of hepatocellular carcinomas in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19454484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Chang1984" class="mim-tip-reference" title="Chang, M.-H., Hsu, H.-C., Lee, C.-Y., Chen, D.-S., Lee, C.-H., Lin, K.-S. <strong>Fraternal hepatocellular carcinoma in young children in two families.</strong> Cancer 53: 1807-1810, 1984.">Chang et al. (1984)</a>; <a href="#Lynch1984" class="mim-tip-reference" title="Lynch, H. T., Srivatanskul, P., Phornthutkul, K., Lynch, J. F. <strong>Familial hepatocellular carcinoma in an endemic area of Thailand.</strong> Cancer Genet. Cytogenet. 11: 11-18, 1984.">Lynch et al. (1984)</a>
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[<a href="https://doi.org/10.1002/1097-0142(19840415)53:8<1807::aid-cncr2820530835>3.0.co;2-j" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.7326/0003-4819-74-3-391" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00273842" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/1097-0142(196911)24:5<1086::aid-cncr2820240535>3.0.co;2-w" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1249484" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMc1308785" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/1097-0142(19870515)59:10<1776::aid-cncr2820591016>3.0.co;2-t" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMc1308785" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/jama.2007.65" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1205591" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0802-339" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41586-019-1607-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000132593" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nm843" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24047073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24047073</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24047073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMc1309091" target="_blank">Full Text</a>]
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Yong, K. J., Gao, C., Lim, J. S. J., Yan, B., Yang, H., Dimitrov, T., Kawasaki, A., Ong, C. W., Wong, K.-F., Lee, S., Ravikumar, S., Srivastava, S., Tian, X., Poon, R. T., Fan, S. T., Luk, J. M., Dan, Y. Y., Salto-Tellez, M., Chai, L., Tenen, D. G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23758232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23758232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23758232[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=23758232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1300297" target="_blank">Full Text</a>]
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Yoo, B. K., Emdad, L., Su, Z., Villanueva, A., Chiang, D. Y., Mukhopadhyay, N. D., Mills, A. S., Waxman, S., Fisher, R. A., Llovet, J. M., Fisher, P. B., Sarkar, D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19221438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19221438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19221438[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=19221438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI36460" target="_blank">Full Text</a>]
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Yoo, B. K., Gredler, R., Vozhilla, N., Su, Z., Chen, D., Forcier, T., Shah, K., Saxena, U., Hansen, U., Fisher, P. B., Sarkar, D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19622726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19622726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19622726[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=19622726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0901451106" target="_blank">Full Text</a>]
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Zhang, H., Zhai, Y., Hu, Z., Wu, C., Qian, J., Jia, W., Ma, F., Huang, W., Yu, L., Yue, W., Wang, Z., Li, P., and 20 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20676096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20676096</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20676096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.638" target="_blank">Full Text</a>]
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Zhou, Y.-Z., Slagle, B. L., Donehower, L. A., vanTuinen, P., Ledbetter, D. H., Butel, J. S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2845134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2845134</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2845134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/JVI.62.11.4224-4231.1988" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/27/2020
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Ada Hamosh - updated : 09/13/2019<br>Ada Hamosh - updated : 05/21/2019<br>Ada Hamosh - updated : 3/31/2014<br>Ada Hamosh - updated : 10/23/2013<br>Ada Hamosh - updated : 7/1/2013<br>Ada Hamosh - updated : 4/15/2013<br>Ada Hamosh - updated : 10/7/2011<br>Ada Hamosh - updated : 9/8/2011<br>George E. Tiller - updated : 11/1/2010<br>Cassandra L. Kniffin - updated : 9/23/2010<br>Cassandra L. Kniffin - updated : 9/20/2010<br>George E. Tiller - updated : 6/28/2010<br>Cassandra L. Kniffin - updated : 11/17/2009<br>Cassandra L. Kniffin - updated : 4/10/2008<br>Cassandra L. Kniffin - updated : 1/28/2008<br>Cassandra L. Kniffin - updated : 11/13/2007<br>Paul J. Converse - updated : 5/14/2007<br>Victor A. McKusick - updated : 9/12/2006<br>George E. Tiller - updated : 2/21/2005<br>Victor A. McKusick - updated : 3/19/2003<br>Victor A. McKusick - updated : 9/16/2002<br>Victor A. McKusick - updated : 9/9/2002<br>Victor A. McKusick - updated : 10/9/2001<br>Victor A. McKusick - updated : 7/21/2000<br>John A. Phillips, III - updated : 7/16/1998
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/27/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 09/13/2019<br>alopez : 09/13/2019<br>alopez : 05/21/2019<br>alopez : 03/31/2014<br>alopez : 3/31/2014<br>alopez : 10/23/2013<br>alopez : 10/23/2013<br>carol : 9/17/2013<br>alopez : 7/1/2013<br>alopez : 4/15/2013<br>terry : 11/13/2012<br>alopez : 10/13/2011<br>terry : 10/7/2011<br>alopez : 9/14/2011<br>terry : 9/8/2011<br>carol : 2/15/2011<br>alopez : 11/3/2010<br>alopez : 11/3/2010<br>terry : 11/1/2010<br>wwang : 10/5/2010<br>ckniffin : 9/23/2010<br>ckniffin : 9/23/2010<br>wwang : 9/22/2010<br>ckniffin : 9/20/2010<br>carol : 8/13/2010<br>wwang : 7/16/2010<br>terry : 6/28/2010<br>wwang : 12/1/2009<br>wwang : 11/20/2009<br>ckniffin : 11/17/2009<br>wwang : 4/16/2008<br>ckniffin : 4/10/2008<br>ckniffin : 2/11/2008<br>carol : 2/5/2008<br>ckniffin : 1/28/2008<br>carol : 1/16/2008<br>wwang : 11/27/2007<br>ckniffin : 11/13/2007<br>mgross : 5/14/2007<br>ckniffin : 9/25/2006<br>terry : 9/12/2006<br>terry : 8/3/2005<br>alopez : 3/22/2005<br>wwang : 3/2/2005<br>terry : 2/21/2005<br>terry : 6/2/2004<br>alopez : 4/1/2003<br>alopez : 3/24/2003<br>terry : 3/19/2003<br>ckniffin : 2/5/2003<br>carol : 9/18/2002<br>carol : 9/18/2002<br>alopez : 9/17/2002<br>carol : 9/16/2002<br>tkritzer : 9/9/2002<br>carol : 10/12/2001<br>terry : 10/9/2001<br>alopez : 7/25/2000<br>terry : 7/21/2000<br>carol : 6/12/1999<br>dkim : 7/24/1998<br>carol : 7/20/1998<br>dholmes : 7/17/1998<br>dholmes : 7/16/1998<br>alopez : 5/14/1998<br>terry : 6/3/1995<br>mark : 5/12/1995<br>mimadm : 4/9/1994<br>carol : 3/31/1992<br>supermim : 3/16/1992<br>carol : 2/28/1992
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 114550
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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HEPATOCELLULAR CARCINOMA
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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HCC<br />
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CANCER, HEPATOCELLULAR<br />
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LIVER CANCER<br />
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LIVER CELL CARCINOMA; LCC<br />
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HEPATOMA
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
|
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HEPATOBLASTOMA, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
|
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|
HEPATOBLASTOMA CAUSED BY SOMATIC MUTATION, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 109841003, 1186630006, 187769009, 25370001, 93870000;
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<strong>ICD10CM:</strong> C22.0, C22.9;
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<strong>ICD9CM:</strong> 155.2;
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<strong>ORPHA:</strong> 210159, 33402, 449, 88673;
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<strong>DO:</strong> 684;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
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</span>
|
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</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">
|
|
2q33.1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114550
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
CASP8
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
601763
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
3p22.1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114550
|
|
</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">
|
|
Hepatocellular carcinoma, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114550
|
|
</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">
|
|
5q22.2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatoblastoma, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114550
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
APC
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
611731
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
6q25.3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114550
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
IGF2R
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
147280
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
7q31.2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, childhood type, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114550
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
MET
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
164860
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
8p22
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular cancer, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114550
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
PDGFRL
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
604584
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
16p13.3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114550
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
AXIN1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
603816
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
17p13.1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hepatocellular carcinoma, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114550
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
TP53
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
191170
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
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<p>A number sign (#) is used with this entry because somatic mutations in a number of different genes have been identified in hepatocellular carcinoma (HCC) and hepatoblastoma. These include TP53 (191170), MET (164860), CTNNB1 (116806), PIK3CA (171834), AXIN1 (603816), and APC (611731).</p><p>See 142330 for familial hepatic adenoma, sometimes associated with hepatocellular carcinoma.</p>
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<strong>Description</strong>
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<p>Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (Taniguchi et al., 2002). </p>
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<strong>Clinical Features</strong>
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<p>Primary cancer of the liver in 3 brothers was described by Kaplan and Cole (1965) and by Hagstrom and Baker (1968). In these patients there was no recognized preexisting liver disease. Denison et al. (1971) described 2 adult brothers who died of primary hepatocellular carcinoma. Both had micronodular cirrhosis with features of subacute progressive viral hepatitis. Australia antigen was demonstrated in the brother in whom it was sought. Their father had died much earlier of hepatocellular carcinoma. </p><p>Hepatoblastoma has been described in sibs (Fraumeni et al., 1969; Napoli and Campbell, 1977; Ito et al., 1987). </p><p>See 231100 for description of liver cancer as a complication of giant cell hepatitis of infancy. Familial liver cell carcinoma might also have its explanation in alpha-1-antitrypsin deficiency (613490), hemochromatosis (235200), and tyrosinemia (276700).</p><p>Jiang et al. (2019) used proteomic and phosphoproteomic profiling to characterize 110 paired tumor and nontumor tissues of clinical early-stage hepatocellular carcinoma related to hepatitis B virus infection. The quantitative proteomic data highlight heterogeneity in early-stage hepatocellular carcinoma. The cohort was stratified into subtypes S-I, S-II, and S-III, each of which has a different clinical outcome. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. </p>
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<strong>Other Features</strong>
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<p>Wang et al. (2019) used a kinome-focused genetic screen to show that pharmacologic inhibition of the DNA-replication kinase CDC7 (603311) induces senescence selectively in liver cancer cells with mutations in TP53 (191170). A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR (601231) signaling, and selective drugs that targeted this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signaling after its inhibition was blocked in cells that had been treated with a CDC7 inhibitor, which led to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, Wang et al. (2019) showed that treatment with combined inhibition of CDC7 and mTOR resulted in a marked reduction of tumor growth. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Somatic Mutations</em></strong></p><p>
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Oda et al. (1996) observed loss of heterozygosity (LOH) at the APC and/or MCC (159350) loci in 4 (57%) of 7 informative hepatoblastoma tissues. Somatic mutations were detected in 8 (61.5%) of the 13 total cases, with 9 cases (69%) showing genetic alterations in the APC gene as LOH or somatic mutations (see, e.g., 611731.0024). Double mutations were demonstrated in 2 cases. The nature of the somatic mutations observed in this study was unusual because 9 of the 10 mutations were missense, with only 1 case featuring a frameshift mutation due to an insertion. By contrast, more than 90% of mutations in the APC gene in colorectal tumors result in a truncated APC protein due to either frameshift or nonsense mutations. </p><p>Thorgeirsson and Grisham (2002) reviewed the molecular pathogenesis of HCC. The malignant phenotype is heterogeneous, and is produced by the disruption of a number of genes that function in different regulatory pathways, producing several molecular variants of HCC. The authors diagrammed the chronologic sequence of cellular events starting with chronic hepatitis from hepatitis B virus (HBV), hepatitis C virus (HCV), and AFB1, which together are responsible for approximately 80% of all HCCS in humans, and proceeding through successive steps of dysplasia and neoplasia. They diagrammed 11 autosome arms in 9 different chromosomes that have been found to contain allelic deletions in more than 30% of reported HCC. Other autosome arms contain allelic deletions in more than 20% of HCC. Heterogeneity of genomic aberrations may reflect the actions of different causative agents. A notable example of an aberration in gene structure related to a specific cause of HCCs is high frequency of the mutation arg249 to ser (191170.0006) of p53 in the tumors of patients chronically exposed to AFB. Thorgeirsson and Grisham (2002) tabulated 14 genes affected by loss of heterozygosity (LOH), mutation, or both in more than 15% of HCCs. </p><p>Activation of wingless (Wnt) signaling through mutations in beta-catenin (CTNNB1; 116806) contributes to the development of HCC and hepatoblastoma (review by Taniguchi et al., 2002). To explore the contribution of additional Wnt pathway molecules to hepatocarcinogenesis, Taniguchi et al. (2002) examined CTNNB1 mutations and mutations in AXIN1 (603816) and AXIN2 (604025) in 73 HCCs and 27 hepatoblastomas. Beta-catenin mutations were detected in 19.2% (14 of 73) HCCs and 70.4% (19 of 27) hepatoblastomas. Beta-catenin mutations in HCCs were primarily point mutations, whereas more than half of the hepatoblastomas had deletions. AXIN1 mutations occurred in 7 (9.6%) HCCs and 2 (7.4%) hepatoblastomas. The AXIN1 mutations included 7 missense mutations, a 1-bp deletion, and a 12-bp insertion. The predominance of missense mutations found in the AXIN1 gene is different from the small deletions or nonsense mutations described previously. Loss of heterozygosity at the AXIN1 locus was present in 4 of 5 informative HCCs with AXIN1 mutations, suggesting a tumor suppressor function for AXIN1. AXIN2 mutations were found in 2 (2.7%) HCCs and in no hepatoblastomas. Two HCCs had both AXIN1 and beta-catenin mutations, and 1 HCC had both AXIN2 and beta-catenin mutations. About half of the HCCs with AXIN1 or AXIN2 mutations showed beta-catenin accumulation in the nucleus, cytoplasm, or membrane. Overall, the data indicated that besides the approximately 20% of HCCs and 80% of hepatoblastomas with beta-catenin mutations contributing to hepatocarcinogenesis, AXIN1 and AXIN2 mutations appear to be important in an additional 10% of HCCs and hepatoblastomas. </p><p>Lee et al. (2005) detected somatic mutations in the PIK3CA gene (see, e.g., 171834.0007; 171834.0008) in 26 (35.6%) of 73 hepatocellular carcinomas. </p><p>Li et al. (2011) performed exome sequencing of 10 HCV-associated HCCs and matched normal tissue from 10 patients and a subsequent evaluation of additional affected individuals, and discovered novel inactivating mutations of ARID2 (609539) in 4 major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC, and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivating mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype. </p><p>Huang et al. (2012) used exome sequencing to identify somatic mutations in 10 hepatitis B virus-positive individuals with hepatocellular carcinoma with portal vein tumor thromboses (PVTTs), intrahepatic metastases. Both C:G-A:T and T:A-A:T transversions were frequently found among the 331 non-silent mutations. Notably, ARID1A (603024), which encodes a component of the SWI/SNF chromatin remodeling complex, was mutated in 14 of 110 (13%) HBV-associated HCC specimens. Huang et al. (2012) used RNA interference to assess the roles of 91 of the confirmed mutated genes in cellular survival. The results suggested that 7 of these genes, including VCAM1 (192225) and CDK14 (610679), may confer growth and infiltration capacity to HCC cells. </p><p><strong><em>Gene Expression Studies</em></strong></p><p>
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Agarwal et al. (1998) reported a case of severe gynecomastia in a 17.5-year-old boy due to high levels of aromatase (CYP19A1; 107910) expression in a large fibrolamellar hepatocellular carcinoma, which caused extremely elevated serum levels of estrone (1200 pg/mL) and estradiol-17 (312 pg/mL) that suppressed follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (1.3 and 2.8 IU/L, respectively) and consequently testosterone (1.53 ng/mL). After removal of the 1.5-kg tumor, gynecomastia partially regressed, and normal hormone levels were restored. By immunohistochemistry, diffuse intracytoplasmic aromatase expression was detected in the liver cancer cells. Northern blot analysis showed P450 aromatase transcripts in total RNA from the hepatocellular cancer but not in the adjacent liver nor in disease-free adult liver samples. Promoters I.3 and II were used for P450 aromatase transcription in the cancer. </p><p>Schwienbacher et al. (2000) analyzed DNA and RNA from 52 human hepatocarcinoma samples and found abnormal imprinting of genes located at 11p15 in 51% of 37 informative samples. The most frequently detected abnormality was gain of imprinting, which led to loss of expression of genes present on the maternal chromosome. As compared with matched normal liver tissue, hepatocellular carcinoma showed extinction or significant reduction of expression of one of the alleles of the CDKN1C (600856), SLC22A1L (602631), and IGF2 (147470) genes. Loss of maternal-specific methylation of the KvDMR1 gene (607542) in hepatocarcinoma correlated with abnormal expression of CDKN1C and IGF2, suggesting a function for KvDMR1 as a long-range imprinting center active in adult tissues. These results pointed to the role of epigenetic mechanisms leading to loss of expression of imprinted genes at 11p15 in human tumors. </p><p>Ye et al. (2003) analyzed the expression profiles of hepatocellular carcinoma samples without or with intrahepatic metastases. Using a supervised machine-learning algorithm, they generated a molecular signature that can classify metastatic HCC patients and identified genes that were relevant to metastasis and patient survival (which is related particularly to intrahepatic metastases). They found that the gene expression signature of primary HCCs with accompanying metastasis was very similar to that of their corresponding metastases, implying that genes favoring metastasis progression were initiated in the primary tumors. Osteopontin (OPN; 166490), which was identified as a lead gene in the signature, was overexpressed in metastatic HCC; an osteopontin-specific antibody effectively blocked HCC in vitro and inhibited pulmonary metastasis of HCC cells in nude mice. Thus, osteopontin acts as both a diagnostic marker and a potential therapeutic target for metastatic HCC. </p><p>Tanabe et al. (2008) reported an association between a 61A-G SNP (rs4444903) in the EGF gene (131530) and the development of hepatocellular carcinoma in patients with cirrhosis. Secretion of EGF was 2.3-fold higher in G/G hepatocellular carcinoma cell lines compared to A/A cell lines, and mRNA transcripts with the G allele showed a longer half-life and increased stability. Among 207 patients with cirrhosis, liver EGF levels were 2.4-fold higher in G/G patients compared to A/A patients. Fifty-nine of the 207 patients with cirrhosis also had hepatocellular carcinoma, and there was a 4-fold increased odds of hepatocellular carcinoma in G/G patients compared with A/A patients. The association was validated in a second cohort of 121 patients with alcoholic cirrhosis and hepatocellular carcinoma. </p><p>Ji et al. (2009) analyzed hepatocellular carcinoma tissue derived from 455 patients from Shanghai and Hong Kong. Most of the patients were men (85.1%), were long-term carriers of the hepatitis B virus (HBV) (90.5%), had cirrhosis (88.0%), and an elevated serum level of alpha-fetoprotein (62.2%). The expression of MIRN26A1 (612151) and MIRN26B (612152) was decreased in tumor tissue compared to non-tumor tissue. Sex stratification showed that women had significantly higher expression of the MIRN26 genes in non-tumor liver tissue compared to men. Gene expression profiling using microarray showed distinct genetic patterns between tumors with low and high MIRN26 expression. The findings were consistent with the MIRN26 genes acting as tumor suppressors. Patients whose tumors showed low MIRN26 expression had shorter overall survival, but better response to interferon therapy compared to patients with higher expression of these MIRNs. </p><p>Yong et al. (2013) screened specimens obtained from 179 patients with hepatocellular carcinoma from Singapore for the expression of SALL4 (607343). SALL4 is an oncofetal protein that is expressed in human fetal liver and silenced in the adult liver, but is reexpressed in a subgroup of patients that have hepatocellular carcinoma with unfavorable prognosis. Gene expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive hepatocellular carcinomas. Yong et al. (2013) found that in a multivariate Cox regression model, SALL4 is an independent prognostic factor for overall survival (hazard ratio for death, 2.87; 95% confidence interval, 1.09 to 7.52; p = 0.03) in the Singapore cohort and an independent predictor of both overall survival (hazard ratio for death, 1.52; 95% confidence interval, 1.00-2.32; p = 0.05) and early recurrence (hazard ratio, 1.67; 95% CI, 1.11-2.51; p = 0.01) in the Hong Kong cohort. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (601728) and inhibited tumor formation in xenograft models in vivo. </p><p>To help avoid additional risks associated with tumor biopsy in patients with SALL4-negative tumors, Hopkins et al. (2013) requested that Yong et al. (2013) determine the sensitivity and specificity of the serum alpha-fetoprotein level in predicting the SALL4 status of their hepatocellular carcinoma patients. Yong et al. (2013) replied that in the Hong Kong cohort of patients with hepatocellular carcinoma they observed a significant correlation between SALL4 mRNA expression and the serum alpha-fetoprotein level (p less than 0.001). The sensitivity and specificity of serum alpha-fetoprotein levels in predicting SALL4 expression in this cohort of 228 patients were calculated to be 66.7% and 68.4%, respectively. The data suggested that with a cutoff value of 100 ng per milliliter, a serum alpha-fetoprotein level of 100 ng per milliliter or more can identify 66.7% of patients with SALL4 mRNA expression. However, 31.6% of patients without SALL4 expression would be falsely identified as being positive for SALL4 expression. Yong et al. (2013) suggested that, to assess SALL4 expression without the need for patient biopsy specimens, a noninvasive assay to test serum SALL4 expression be developed. </p><p>Suzuki et al. (2013) asked of Yong et al. (2013) whether the unfavorable clinical outcome in high-SALL4 hepatocellular carcinoma is attributable to features of cholangiocarcinoma. Masuda et al. (2013) inquired whether reprogramming factors such as KLF5 or TBX3 could be involved in the pathogenesis of SALL4-related hepatocellular carcinoma, and if reexpression of SALL4 through hepatitis B infection has a role in upregulation of SALL4. Yong et al. (2013) replied that more studies would be necessary to address these queries. </p><p><strong><em>Hepatitis B Infection</em></strong></p><p>
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Integration of HBV into cellular DNA occurs during long-term persistent infection in man. Hepatocellular carcinomas isolated from carriers of virus often contain clonally propagated viral DNA. Shen et al. (1991) presented evidence for the interaction of inherited susceptibility and hepatitis B viral infection in cases of primary hepatocellular carcinoma in eastern China. Complex segregation analysis of 490 extended families supported the existence of a recessive allele with population frequency approximately 0.25, which results in a lifetime risk of HCC in the presence of both HBV infection and genetic susceptibility, of 0.84 for males and 0.46 for females. The model further predicted that, in the absence of genetic susceptibility, lifetime risk of HCC is 0.09 for HBV-infected males and 0.01 for HBV-infected females and that regardless of genotype the risk is virtually zero for uninfected persons. </p><p>The finding of small deletions in retinoblastoma and Wilms tumor prompted Rogler et al. (1985) to look for the same in association with HBV integration in hepatocellular carcinoma. They demonstrated a deletion of at least 13.5 kb of cellular sequences in a liver cancer. The HBV integration and the deletion occurred on the short arm of chromosome 11 at location 11p14-p13. The deleted sequences were lost in tumor cells leaving only a single copy. Clones of the DNA flanking the deleted segment were used for the mapping of the deletion in somatic cell hybrids and by in situ hybridization. Cellular sequences homologous to the deleted region were cloned and used to exclude the possibility that this DNA had been moved to other positions in the genome. Fisher et al. (1987) extended the observations of Rogler et al. (1985). Using somatic cell hybrids that contained defined 11p deletions, 2 cloned DNA sequences that flank the deletion generated by a hepatocellular carcinoma (as a consequence of hepatitis B virus integration) were mapped to 11p13. Wilms tumor (194070) and the tumors of Beckwith-Wiedemann syndrome (130650) are also determined by changes on 11p. Wang and Rogler (1988) found loss of heterozygosity in 11p and 13q. </p><p>Integration of DNA from the hepatitis B virus has been shown to occur frequently in human hepatocellular carcinomas. Recombinant DNA probes have been isolated from such a tumor. These probes detected rearrangements of the corresponding DNA domain in 10% of liver tumors regardless of whether they were HBV-related or not (Pasquinelli et al., 1988). Blanquet et al. (1987, 1988) cloned the normal allele and used it for mapping an HCC locus by somatic cell hybrid studies and by in situ hybridization. These experiments showed that the locus is located in the area 4q32.1. Buetow et al. (1989) found that 7 of 11 primary liver tumors tested against a panel of RFLPs demonstrated loss of constitutional heterozygosity for markers on chromosome 4, particularly 4q. Buetow et al. (1989) suggested that chronic hepatitis B virus infection and other environmental agents may operate through genetic events leading to loss of a tumor suppressor locus (anti-oncogene) on chromosome 4. The findings were thought to be consistent with those of Pasquinelli et al. (1988), which placed the critical region in the vicinity of 4q32. </p><p>Smith et al. (1989) gave evidence for microdeletions of chromosome 4q involving the alcohol dehydrogenase isoenzyme gene ADH3 (ADH1C; 103730) and hepatomas from 3 of 5 individuals heterozygous for an XbaI RFLP detectable by the ADH probe. Two of 7 individuals heterozygous for an epidermal growth factor RFLP had lost 1 EGF allele in their hepatoma tissue.</p><p>Henderson et al. (1988) demonstrated that the integration of HBV DNA can result in, or be accompanied by, interchromosomal exchange of genomic material containing the integrated DNA. Using in situ hybridization, they found that unique cellular DNA to the left of an HBV DNA integration site, cloned from a primary tumor, mapped to chromosome 18q (18q11.1-q11.2); right-hand flanking DNA mapped to chromosome 17 (17q22-q25). </p><p>In a hepatoma specimen from Shanghai, Zhou et al. (1988) identified integration of hepatitis B virus into 17p12-p11.2, which is near the human protooncogene p53 (191170). Furthermore, the sequence of flanking cellular DNA showed highly significant homology with a conserved region of a number of functional mammalian DNAs, including the human autonomously replicated sequence-1 (ARS1; 109110). ARS1 is a sequence of human DNA that allows replication of Saccharomyces cerevisiae integrative plasmids as autonomously replicating elements in S. cerevisiae cells. Since integration of viral DNA is not a required step in the replicative cycle of the hepatitis virus, the presence of integrated HBV sequences in many human hepatocellular carcinomas suggests a causal relationship. Since any 1 of several integration sites may lead to the same result, the crucial cellular targets involved in triggering liver cell malignant transformation may differ from tumor to tumor. </p><p>Primary hepatocellular carcinoma occurs at high frequencies in east Asia and sub-Saharan Africa. In these areas of the world, chronic infection with the hepatitis B virus is the best documented risk factor; however, only 20 to 25% of HBV carriers develop HCC. Exposure to the fungal toxin aflatoxin B1 (AFB1) has been suggested to increase HCC risk, in part because in vitro experiments demonstrated that AFB1 mutagenic metabolites bind to DNA and are capable of inducing G-to-T transversions. In certain areas of the HCC endemic regions, a mutation hotspot has been reported in the p53 tumor suppressor gene (TP53; 191170): an AGG-to-AGT transversion (arginine to serine) of codon 249 in exon 7 (191170.0006). Microsomal epoxide hydrolase (EPHX; 132810) and glutathione-S-transferase M1 (GSTM1; 138350) are both involved in AFB1 detoxification in hepatocytes. Polymorphism of both genes has been identified. In Ghana and China, McGlynn et al. (1995) conducted studies to determine whether mutant alleles at one or both of these loci are associated with increased levels of serum AFB1-albumin adducts, with HCC, and with mutations at codon 249 of p53. In a cross-sectional study, they found that mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1 albumin adducts. Additionally, in a case-control study, mutant alleles of EPHX were significantly overrepresented in persons with HCC. The relationship of EPHX to HCC varied by hepatitis B surface antigen status, indicating that a synergistic effect may exist. Mutations at codon 249 of p53 were observed only among HCC patients with one or both high-risk genotypes. These findings by McGlynn et al. (1995) supported the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicated that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype. </p><p>Chiu et al. (2007) examined the roles of androgen receptor (AR; 313700) and the HBV nonstructural protein HBx in hepatocellular carcinoma, a disease that predominantly affects males. HBx increased the anchorage-independent colony formation potency of AR in a nontransformed mouse hepatocyte cell line. AR-mediated transcriptional activity was enhanced by HBx in an androgen concentration-dependent manner. Mutation analysis showed that HBx-enhanced AR gene transcriptional activity required intact HBx and the hinge region of AR. Immunoprecipitation and cell fractionation analyses revealed that HBx-AR interactions occurred mainly in the cytosol. HBx-enhanced AR activation involved SRC (190090) activity. Chiu et al. (2007) concluded that HBx is a noncellular positive coregulator of AR. </p><p><strong><em>Glycogen Storage Disease Type Ia</em></strong></p><p>
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Hepatocellular adenoma (HCA) is a frequent long-term complication of glycogen storage disease type I (GSD I; 232200), and malignant transformation to hepatocellular carcinoma (HCC) occurs in some cases. Kishnani et al. (2009) performed genomewide SNP analysis and mutation detection of target genes in 10 GSD Ia-associated HCA and 7 general population HCA cases. Chromosomal aberrations were detected in 60% of the GSD Ia HCA and 57% of general population HCA. Coincident gain of chromosome 6p and loss of 6q were seen only in GSD Ia HCA (3 cases) with 1 additional GSD I patient showing submicroscopic 6q14.1 deletion. The sizes of GSD Ia adenomas with chromosome 6 aberrations were larger than the sizes of adenomas without the changes (P = 0.012). Expression of IGF2R (FCGR2A; 146790) and LATS1 (603473) candidate tumor suppressor genes at 6q was reduced in more than 50% of 7 GSD Ia HCA examined. None of the GSD Ia HCA had biallelic mutations in the HNF1A (142410) gene. The authors suggested that chromosome 6 alterations could be an early event in the liver tumorigenesis in GSD I, and possibly in general population. </p><p><strong><em>Associations with HCC in Chronic HBV Carriers Pending Confirmation</em></strong></p><p>
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By means of genetic association analysis, Shin et al. (2003) showed that the interleukin-10 (IL10; 124092) haplotype IL10-ht2 was strongly associated with hepatocellular carcinoma in a well-characterized HBV cohort. The frequency of susceptible IL10-ht2 was much higher in HCC patients and significantly increased in order of susceptibility to HBV progression from chronic hepatitis to liver cirrhosis and HCC among hepatitis B patients. In addition, survival analysis showed that the onset age of HCC was also accelerated among chronic hepatitis B patients who were carrying IL10-ht2. Shin et al. (2003) suggested that increased IL10 production mediated by IL10-ht2 accelerates progression of chronic HBV infection, especially to HCC development. </p><p>In a genomewide association study of 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry, Zhang et al. (2010) found an association between HBV-related HCC and a SNP (rs17401966) in an intron of the KIF1B gene (605995) on chromosome 1p36.22. The association was confirmed in 5 additional independent Chinese samples, consisting of 1,962 individuals with HCC, 1,430 control subjects, and 159 family trios. Across all 6 studies, the combined p value for the protective G allele of rs17401966 was 1.7 x 10(-18), with an odds ratio of 0.61. </p><p><strong><em>Associations with HCC in Chronic HCV Carriers Pending Confirmation</em></strong></p><p>
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Kumar et al. (2011) conducted a genomewide association study using 432,703 autosomal SNPs in 721 individuals with HCV-induced HCC and 2,890 HCV-negative controls of Japanese origin. Eight SNPs that showed possible association in the genomewide association study were further genotyped in 673 cases and 2,596 controls. Kumar et al. (2011) found a previously unidentified locus in the 5-prime flanking region of MICA (600169) on 6p21.33 (rs2596542, combined p = 4.21 x 10(-13), odds ratio = 1.39) to be strongly associated with HCV-induced HCC. Subsequent analyses using individuals with chronic hepatitis C (CHC) indicated that this SNP is not associated with CHC susceptibility but is significantly associated with progression from CHC to HCC (p = 3.13 x 10(-8)). Kumar et al. (2011) also found that the risk allele of rs2596542 was associated with lower soluble MICA protein levels in individuals with HCV-induced HCC (p = 1.38 x 10(-13)). </p>
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<p>Yoo et al. (2009) found that expression of AEG1 (MTDH; 610323) was significantly elevated in hepatocellular carcinomas compared with normal human hepatocytes. Stable expression of AEG1 increased the aggressiveness of nontumorigenic human HCC cells, and inhibition of AEG1 abrogated tumorigenesis by aggressive HCC cells in a xenograft model of nude mice. In humans, AEG1 overexpression was associated with elevated copy number. Microarray analysis revealed that AEG1 modulated the expression of genes associated with invasion, metastasis, chemoresistance, angiogenesis, and senescence. AEG1 specifically activated Wnt (see 164820)/beta-catenin (CTNNB1; 116806) signaling, resulting in upregulation of LEF1 (153245), the ultimate executor of the Wnt signaling pathway. AEG1 also activated the NF-kappa-B (see 164011) pathway, which may play a role in the chronic inflammatory changes preceding HCC development. Yoo et al. (2009) concluded that AEG1 plays a central role in HCC pathogenesis. </p><p>By cDNA microarray, Western blot analysis, and luciferase constructs, Yoo et al. (2009) found significant upregulation of the transcription factor LSF (TFCP2; 189889) and increased LSF transcriptional activity in the nuclei of hepatocellular carcinoma cells expressing AEG1 compared to those without AEG1 expression. The increase in LSF activity correlated with significant increases in the downstream targets thymidylate synthetase (TYMS; 188350) during the growth cycle and dihydropyrimidine dehydrogenase (DPYD; 612779). The AEG1-transfected HCC cells showed more resistance to 5-fluorouracil (5-FU) treatment compared to those without AEG1 expression, which could be explained by the upregulation of both TYMS and DPYD. Studies with siRNA targeting AEG1, LSF, or DPYD abrogated the 5-FU resistance. In nude xenograft mice transfected with an HCC cell line that expressed AEG1 and showed resistance to 5-FU, inhibition of AEG1 resulted in significant inhibition in tumor growth, and a combination of 5-FU and AEG1 inhibition resulted in an additive effect on tumor growth inhibition. The findings demonstrated that AEG1 confers resistance to 5-FU by inducing the expression of LSF and DPYD, and pointed to a central role of AEG1 in HCC development and progression. </p><p>The S-III subtype of hepatitis B-related hepatocellular carcinoma is characterized by disrupted cholesterol homeostasis, and is associated with the lowest overall rate of survival among the 3 subtypes characterized by Jiang et al. (2019) and the greatest risk of a poor prognosis after first-line surgery. Jiang et al. (2019) found that knockdown of sterol O-acyltransferase-1 (SOAT1; 102642), high expression of which is a signature specific to the S-III subtype, altered the distribution of cellular cholesterol, and effectively suppressed the proliferation and migration of hepatocellular carcinoma. On the basis of a patient-derived tumor xenograft mouse model of hepatocellular carcinoma, Jiang et al. (2019) found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumors that had high levels of SOAT1 expression. </p><p>HCC and intrahepatic cholangiocarcinoma (ICC; 615619) differ markedly with regards to their morphology, metastatic potential, and responses to therapy. Seehawer et al. (2018) demonstrated that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 (601621) and Prdm5 (614161) as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Seehawer et al. (2018) concluded that their results provided insight into lineage commitment in liver tumorigenesis, and explained molecularly why common liver-damaging risk factors can lead to either HCC or ICC. </p><p><strong><em>Fibrolamellar Hepatocellular Carcinoma</em></strong></p><p>
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Fibrolamellar HCC is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis. Honeyman et al. (2014) identified a chimeric transcript that is expressed in fibrolamellar HCC but not in adjacent normal liver and that arises as the result of an approximately 400-kb deletion on chromosome 19. The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1 (604572), a homolog of the molecular chaperone DNAJ, fused in-frame with PRKACA (601639), the catalytic domain of protein kinase A. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the fibrolamellar HCCs examined (15 of 15) suggests that this genetic alteration contributes to tumor pathogenesis. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<p>Hill-Baskin et al. (2009) tested the long-term effects of high- and low-fat diets on male mice of 2 inbred strains and discovered that C57BL/6J but not A/J male mice were susceptible to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) on a high- but not low-fat diet. Susceptible mice showed morphologic characteristics of NASH (steatosis, hepatitis, fibrosis, and cirrhosis), dysplasia, and HCC. The mRNA profiles of HCCs versus tumor-free liver showed involvement of 2 signaling networks, one centered on Myc (190080) and the other on NFKB1 (164011), similar to signaling described for the 2 major classes of HCC in humans. The miRNA profiles revealed dramatically increased expression of a cluster of miRNAs on the X chromosome without amplification of the chromosomal segment. A switch from high- to low-fat diet reversed these outcomes, with switched C57BL/6J males being lean rather than obese and without evidence for NASH or HCCs at the end of the study. A similar diet modification may have important implications for prevention of hepatocellular carcinomas in humans. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Chang et al. (1984); Lynch et al. (1984)
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<div>
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<h4>
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Ada Hamosh - updated : 03/27/2020<br>Ada Hamosh - updated : 09/13/2019<br>Ada Hamosh - updated : 05/21/2019<br>Ada Hamosh - updated : 3/31/2014<br>Ada Hamosh - updated : 10/23/2013<br>Ada Hamosh - updated : 7/1/2013<br>Ada Hamosh - updated : 4/15/2013<br>Ada Hamosh - updated : 10/7/2011<br>Ada Hamosh - updated : 9/8/2011<br>George E. Tiller - updated : 11/1/2010<br>Cassandra L. Kniffin - updated : 9/23/2010<br>Cassandra L. Kniffin - updated : 9/20/2010<br>George E. Tiller - updated : 6/28/2010<br>Cassandra L. Kniffin - updated : 11/17/2009<br>Cassandra L. Kniffin - updated : 4/10/2008<br>Cassandra L. Kniffin - updated : 1/28/2008<br>Cassandra L. Kniffin - updated : 11/13/2007<br>Paul J. Converse - updated : 5/14/2007<br>Victor A. McKusick - updated : 9/12/2006<br>George E. Tiller - updated : 2/21/2005<br>Victor A. McKusick - updated : 3/19/2003<br>Victor A. McKusick - updated : 9/16/2002<br>Victor A. McKusick - updated : 9/9/2002<br>Victor A. McKusick - updated : 10/9/2001<br>Victor A. McKusick - updated : 7/21/2000<br>John A. Phillips, III - updated : 7/16/1998
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Victor A. McKusick : 6/4/1986
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alopez : 03/27/2020<br>alopez : 09/13/2019<br>alopez : 09/13/2019<br>alopez : 05/21/2019<br>alopez : 03/31/2014<br>alopez : 3/31/2014<br>alopez : 10/23/2013<br>alopez : 10/23/2013<br>carol : 9/17/2013<br>alopez : 7/1/2013<br>alopez : 4/15/2013<br>terry : 11/13/2012<br>alopez : 10/13/2011<br>terry : 10/7/2011<br>alopez : 9/14/2011<br>terry : 9/8/2011<br>carol : 2/15/2011<br>alopez : 11/3/2010<br>alopez : 11/3/2010<br>terry : 11/1/2010<br>wwang : 10/5/2010<br>ckniffin : 9/23/2010<br>ckniffin : 9/23/2010<br>wwang : 9/22/2010<br>ckniffin : 9/20/2010<br>carol : 8/13/2010<br>wwang : 7/16/2010<br>terry : 6/28/2010<br>wwang : 12/1/2009<br>wwang : 11/20/2009<br>ckniffin : 11/17/2009<br>wwang : 4/16/2008<br>ckniffin : 4/10/2008<br>ckniffin : 2/11/2008<br>carol : 2/5/2008<br>ckniffin : 1/28/2008<br>carol : 1/16/2008<br>wwang : 11/27/2007<br>ckniffin : 11/13/2007<br>mgross : 5/14/2007<br>ckniffin : 9/25/2006<br>terry : 9/12/2006<br>terry : 8/3/2005<br>alopez : 3/22/2005<br>wwang : 3/2/2005<br>terry : 2/21/2005<br>terry : 6/2/2004<br>alopez : 4/1/2003<br>alopez : 3/24/2003<br>terry : 3/19/2003<br>ckniffin : 2/5/2003<br>carol : 9/18/2002<br>carol : 9/18/2002<br>alopez : 9/17/2002<br>carol : 9/16/2002<br>tkritzer : 9/9/2002<br>carol : 10/12/2001<br>terry : 10/9/2001<br>alopez : 7/25/2000<br>terry : 7/21/2000<br>carol : 6/12/1999<br>dkim : 7/24/1998<br>carol : 7/20/1998<br>dholmes : 7/17/1998<br>dholmes : 7/16/1998<br>alopez : 5/14/1998<br>terry : 6/3/1995<br>mark : 5/12/1995<br>mimadm : 4/9/1994<br>carol : 3/31/1992<br>supermim : 3/16/1992<br>carol : 2/28/1992
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