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Entry
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- #605027 - LYMPHOMA, NON-HODGKIN, FAMILIAL
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- OMIM
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<p>
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<span class="h4">#605027</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="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#inheritance">Inheritance</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</h4>
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<div><a href="https://clinicaltrials.gov/search?cond=(LYMPHOMA, NON-HODGKIN, FAMILIAL) OR (BCL10 OR RAD54L OR CASP10 OR RAD54B OR PRF1)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3765&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8403" 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=605027[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=547" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div style="display: table-cell;">Animal Models</div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0060060" 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/605027" 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/OMIA001708/" 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:0060060" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 547<br />
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<strong>DO:</strong> 0060060<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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605027
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</span>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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LYMPHOMA, NON-HODGKIN, FAMILIAL
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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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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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NON-HODGKIN LYMPHOMA; NHL
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/1/567?start=-3&limit=10&highlight=567">
|
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1p34.1
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Lymphoma, non-Hodgkin, somatic
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/605027"> 605027 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
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RAD54L
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/603615"> 603615 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/763?start=-3&limit=10&highlight=763">
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1p22.3
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Lymphoma, follicular, somatic}
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/605027"> 605027 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
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BCL10
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<p>A number sign (#) is used with this entry because non-Hodgkin lymphoma is associated with somatic mutations in a number of genes, including CASP10 (<a href="/entry/601762">601762</a>), ATM (<a href="/entry/607585">607585</a>), RAD54L (<a href="/entry/603615">603615</a>), BRAF (<a href="/entry/164757">164757</a>), CARD11 (<a href="/entry/607210">607210</a>), and RAD54B (<a href="/entry/604289">604289</a>).</p>
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<p><a href="#10" class="mim-tip-reference" title="Wiernik, P. H., Wang, S. Q., Hu, X.-P., Marino, P., Paietta, E. <strong>Age of onset evidence for anticipation in familial non-Hodgkin's lymphoma.</strong> Brit. J. Haemat. 108: 72-79, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10651726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10651726</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.01815.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10651726">Wiernik et al. (2000)</a> analyzed 11 published reports of multigenerational familial non-Hodgkin lymphoma (NHL) and 18 previously unreported families with familial NHL for evidence of anticipation. They determined the difference in disease-free survival between generations and the difference in the age of onset for each affected parent-child pair. To avoid ascertainment bias, the analyses were also performed separately using only parent-child pairs with age of onset greater than 25 years. In addition, the age-of-onset distribution of the studied cases was compared with that of the Surveillance Epidemiology and End Results (SEER) program using data for 1973 to 1998. The median age of onset in the child and parent generations of all families (48.5 and 78.3 years, respectively) and in the selected pairs (52.5 and 71.5 years, respectively) was significantly different. A significant difference was observed between the ages of onset between the child generation and that of the SEER population but not between the parent generation and the SEER population. <a href="#10" class="mim-tip-reference" title="Wiernik, P. H., Wang, S. Q., Hu, X.-P., Marino, P., Paietta, E. <strong>Age of onset evidence for anticipation in familial non-Hodgkin's lymphoma.</strong> Brit. J. Haemat. 108: 72-79, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10651726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10651726</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.01815.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10651726">Wiernik et al. (2000)</a> concluded that anticipation in familial NHL is a genuine phenomenon and suggests a genetic role in the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10651726" 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>Using the Swedish Family-Cancer Database, <a href="#1" class="mim-tip-reference" title="Altieri, A., Bermejo, J. L., Hemminki, K. <strong>Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database.</strong> Blood 106: 668-672, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15811955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15811955</a>] [<a href="https://doi.org/10.1182/blood-2005-01-0140" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15811955">Altieri et al. (2005)</a> calculated standardized incidence ratios (SIRs) for histopathology-specific subtypes of NHL in 4,455 offspring with NHL whose parents or sibs were affected with different types of lymphoproliferative malignancies. SIRs for affected patients with a parental history of NHL were significantly increased for NHL (1.8) and diffuse large B-cell lymphoma (2.3). SIRs for affected patients with a sib history of NHL were significantly increased for NHL (1.9), follicular lymphoma (2.3), and B-cell lymphoma not otherwise specified (3.4). With a parental history of histopathology-specific concordant cancer, familial risks were significantly increased for diffuse large B-cell lymphoma, follicular NHL, plasma cell myeloma, and chronic lymphocytic leukemia (SIRs of 11.8, 6.1, 2.5, and 5.9, respectively). <a href="#1" class="mim-tip-reference" title="Altieri, A., Bermejo, J. L., Hemminki, K. <strong>Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database.</strong> Blood 106: 668-672, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15811955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15811955</a>] [<a href="https://doi.org/10.1182/blood-2005-01-0140" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15811955">Altieri et al. (2005)</a> concluded that there is a strong familial association in NHL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15811955" 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>Roughly 10% of activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCLs) have mutant CARD11 (<a href="/entry/607210">607210</a>) isoforms that activate NF-kappa-B (see <a href="/entry/164011">164011</a>). <a href="#4" class="mim-tip-reference" title="Davis, R. E., Ngo, V. N., Lenz, G., Tolar, P., Young, R. M., Romesser, P. B., Kohlhammer, H., Lamy, L., Zhao, H., Yang, Y., Xu, W., Shaffer, A. L., and 25 others. <strong>Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.</strong> Nature 463: 88-92, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20054396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20054396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20054396[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20054396">Davis et al. (2010)</a> used an RNA interference genetic screen to show that the BCR signaling component Bruton tyrosine kinase (BTK; <a href="/entry/300300">300300</a>) is essential for the survival of ABC DLBCLs with wildtype CARD11. In addition, knockdown of proximal BCR subunits (IgM, see <a href="/entry/147020">147020</a>; Ig-kappa, see <a href="/entry/147200">147200</a>; CD79A, <a href="/entry/112205">112205</a>; and CD79B, <a href="/entry/147245">147245</a>) killed ABC DLBCLs with wildtype CARD11 but not other lymphomas. The B cell receptors in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signaling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine at position 196, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase (<a href="/entry/165120">165120</a>), a feedback inhibitor of BCR signaling. <a href="#4" class="mim-tip-reference" title="Davis, R. E., Ngo, V. N., Lenz, G., Tolar, P., Young, R. M., Romesser, P. B., Kohlhammer, H., Lamy, L., Zhao, H., Yang, Y., Xu, W., Shaffer, A. L., and 25 others. <strong>Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.</strong> Nature 463: 88-92, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20054396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20054396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20054396[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20054396">Davis et al. (2010)</a> concluded that their findings establish chronic active BCR signaling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20054396" 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="#2" class="mim-tip-reference" title="Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G. <strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong> Blood 105: 4424-4428, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728124</a>] [<a href="https://doi.org/10.1182/blood-2004-04-1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15728124">Clementi et al. (2005)</a> reported 4 patients with non-Hodgkin lymphoma with features of hemophagocytic lymphohistiocytosis (<a href="/entry/603533">603533</a>) who had mutations in the perforin gene (see <a href="/entry/170280#0002">170280.0002</a>; <a href="/entry/170280#0009">170280.0009</a>; <a href="/entry/170280#0011">170280.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15728124" 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>DLBCL is the most common form of non-Hodgkin lymphoma, accounting for 30 to 40% of cases (<a href="#5" class="mim-tip-reference" title="Lenz, G., Davis, R. E., Ngo, V. N., Lam, L., George, T. C., Wright, G. W., Dave, S. S., Zhao, H., Xu, W., Rosenwald, A., Ott, G., Muller-Hermelink, H. K., and 10 others. <strong>Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.</strong> Science 319: 1676-1679, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18323416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18323416</a>] [<a href="https://doi.org/10.1126/science.1153629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18323416">Lenz et al., 2008</a>). DLBCL consists of 3 subtypes: germinal center B cell-like (GCB) DLBCL, ABC DLBCL, and primary mediastinal B cell lymphoma. The ABC DLBCL subtype accounts for roughly one-third of the cases and has an inferior prognosis. A characteristic feature of ABC DLBCL is constitutive activation of the NF-kappa-B (see <a href="/entry/164011">164011</a>) pathway, which plays a pivotal role in proliferation, differentiation, and survival of normal lymphoid cells. In normal B cells, antigen receptor-induced NF-kappa-B activation requires CARD11 (<a href="/entry/607210">607210</a>), a cytoplasmic scaffolding protein. To determine whether CARD11 contributes to tumorigenesis, <a href="#5" class="mim-tip-reference" title="Lenz, G., Davis, R. E., Ngo, V. N., Lam, L., George, T. C., Wright, G. W., Dave, S. S., Zhao, H., Xu, W., Rosenwald, A., Ott, G., Muller-Hermelink, H. K., and 10 others. <strong>Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.</strong> Science 319: 1676-1679, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18323416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18323416</a>] [<a href="https://doi.org/10.1126/science.1153629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18323416">Lenz et al. (2008)</a> sequenced the CARD11 gene in human DLBCL tumors. <a href="#5" class="mim-tip-reference" title="Lenz, G., Davis, R. E., Ngo, V. N., Lam, L., George, T. C., Wright, G. W., Dave, S. S., Zhao, H., Xu, W., Rosenwald, A., Ott, G., Muller-Hermelink, H. K., and 10 others. <strong>Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.</strong> Science 319: 1676-1679, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18323416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18323416</a>] [<a href="https://doi.org/10.1126/science.1153629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18323416">Lenz et al. (2008)</a> detected missense mutations in 7 of 73 ABC DLBCL biopsies (9.6%), all within exons encoding the coiled-coil domain. Experimental introduction of CARD11 coiled-coil domain mutants into lymphoma cell lines resulted in constitutive NF-kappa-B activation and enhanced the NF-kappa-B activity upon antigen receptor stimulation. <a href="#5" class="mim-tip-reference" title="Lenz, G., Davis, R. E., Ngo, V. N., Lam, L., George, T. C., Wright, G. W., Dave, S. S., Zhao, H., Xu, W., Rosenwald, A., Ott, G., Muller-Hermelink, H. K., and 10 others. <strong>Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.</strong> Science 319: 1676-1679, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18323416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18323416</a>] [<a href="https://doi.org/10.1126/science.1153629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18323416">Lenz et al. (2008)</a> concluded that CARD11 is a bona fide oncogene in DLBCL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18323416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Compagno, M., Lim, W. K., Grunn, A., Nandula, S. V., Brahmachary, M., Shen, Q., Bertoni, F., Ponzoni, M., Scandurra, M., Califano, A., Bhagat, G., Chadburn, A., Dalla-Favera, R., Pasqualucci, L. <strong>Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.</strong> Nature 459: 717-721, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412164[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07968" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412164">Compagno et al. (2009)</a> showed that greater than 50% of ABC DLBCL and a smaller fraction of germinal center B cell-like (GCB) DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3; <a href="/entry/191163">191163</a>) and positive (including CARD11 and TRAF2, <a href="/entry/601895">601895</a>) regulators of NF-kappa-B. Of these, the TNFAIP3 gene, which encodes a ubiquitin-modifying enzyme (A20) involved in termination of NF-kappa-B responses, is most commonly affected, with approximately 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumor suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kappa-B. <a href="#3" class="mim-tip-reference" title="Compagno, M., Lim, W. K., Grunn, A., Nandula, S. V., Brahmachary, M., Shen, Q., Bertoni, F., Ponzoni, M., Scandurra, M., Califano, A., Bhagat, G., Chadburn, A., Dalla-Favera, R., Pasqualucci, L. <strong>Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.</strong> Nature 459: 717-721, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412164[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07968" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412164">Compagno et al. (2009)</a> concluded that NF-kappa-B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappa-B responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19412164" 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="Morin, R. D., Johnson, N. A., Severson, T. M., Mungall, A. J., An, J., Goya, R., Paul, J. E., Boyle, M., Woolcock, B. W., Kuchenbauer, F., Yap, D., Humphries, R. K., and 26 others. <strong>Somatic mutations altering EZH2 (tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.</strong> Nature Genet. 42: 181-185, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20081860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20081860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20081860[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20081860">Morin et al. (2010)</a> identified recurrent somatic mutations affecting the tyr641 residue of the conserved SET domain in the EZH2 gene (<a href="/entry/601573">601573</a>) in cases of follicular lymphoma and diffuse large B-cell lymphoma of only the GCB subtype. Their data indicated that mutation involving this tyrosine was among the most frequent genetic events observed in GCB malignancies, after t(14;18)(q32;q21) translocations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20081860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Pasqualucci, L., Dominguez-Sola, D., Chiarenza, A., Fabbri, G., Grunn, A., Trifonov, V., Kasper, L. H., Lerach, S., Tang, H., Ma, J., Rossi, D., Chadburn, A., Murty, V. V., Mullighan, C. G., Gaidano, G., Rabadan, R., Brindle, P. K., Dalla-Favera, R. <strong>Inactivating mutations of acetyltransferase genes in B-cell lymphoma.</strong> Nature 471: 189-195, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21390126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21390126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21390126[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09730" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21390126">Pasqualucci et al. (2011)</a> reported that the 2 most common types of B cell non-Hodgkin lymphoma, follicular lymphoma and diffuse large B-cell lymphoma, harbor frequent structural alterations inactivating CREBBP (<a href="/entry/600140">600140</a>) and, more rarely, EP300 (<a href="/entry/602700">602700</a>), 2 highly related histone and nonhistone acetyltransferases (HATs) that act as transcriptional coactivators in multiple signaling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these 2 genes. These lesions usually affect 1 allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. <a href="#8" class="mim-tip-reference" title="Pasqualucci, L., Dominguez-Sola, D., Chiarenza, A., Fabbri, G., Grunn, A., Trifonov, V., Kasper, L. H., Lerach, S., Tang, H., Ma, J., Rossi, D., Chadburn, A., Murty, V. V., Mullighan, C. G., Gaidano, G., Rabadan, R., Brindle, P. K., Dalla-Favera, R. <strong>Inactivating mutations of acetyltransferase genes in B-cell lymphoma.</strong> Nature 471: 189-195, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21390126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21390126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21390126[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09730" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21390126">Pasqualucci et al. (2011)</a> demonstrated specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein (<a href="/entry/109565">109565</a>) and activation of the p53 tumor suppressor (<a href="/entry/191170">191170</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21390126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Morin, R. D., Mendez-Lago, M., Mungall, A. J., Goya, R., Mungall, K. L., Corbett, R. D., Johnson, N. A., Severson, T. M., Chiu, R., Field, M., Jackman, S., Krzywinski, M., and 38 others. <strong>Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma.</strong> Nature 476: 298-303, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21796119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21796119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21796119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21796119">Morin et al. (2011)</a> sequenced tumor and matched control DNA from 13 DLBCL cases and 1 follicular lymphoma case to identify genes with mutations in B-cell NHL. <a href="#7" class="mim-tip-reference" title="Morin, R. D., Mendez-Lago, M., Mungall, A. J., Goya, R., Mungall, K. L., Corbett, R. D., Johnson, N. A., Severson, T. M., Chiu, R., Field, M., Jackman, S., Krzywinski, M., and 38 others. <strong>Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma.</strong> Nature 476: 298-303, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21796119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21796119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21796119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21796119">Morin et al. (2011)</a> analyzed RNA sequencing data from these and another 113 NHLs to identify genes with candidate mutations, and then resequenced tumor and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of follicular lymphoma cases had somatic mutations in MLL2 (<a href="/entry/602113">602113</a>), which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and follicular lymphoma cases, respectively, had mutations in MEF2B (<a href="/entry/601661">601661</a>), a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. <a href="#7" class="mim-tip-reference" title="Morin, R. D., Mendez-Lago, M., Mungall, A. J., Goya, R., Mungall, K. L., Corbett, R. D., Johnson, N. A., Severson, T. M., Chiu, R., Field, M., Jackman, S., Krzywinski, M., and 38 others. <strong>Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma.</strong> Nature 476: 298-303, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21796119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21796119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21796119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21796119">Morin et al. (2011)</a> concluded that their analysis suggested a previously unappreciated disruption of chromatin biology in lymphomagenesis. In their analysis, <a href="#7" class="mim-tip-reference" title="Morin, R. D., Mendez-Lago, M., Mungall, A. J., Goya, R., Mungall, K. L., Corbett, R. D., Johnson, N. A., Severson, T. M., Chiu, R., Field, M., Jackman, S., Krzywinski, M., and 38 others. <strong>Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma.</strong> Nature 476: 298-303, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21796119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21796119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21796119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21796119">Morin et al. (2011)</a> found that the 8 most significant genes included 7 with strong selective pressure for nonsense mutations, including the known tumor suppressor genes TP53 and TNFRSF14 (<a href="/entry/602746">602746</a>). CREBBP also showed some evidence for acquisition of nonsense mutations and coding single-nucleotide variants. <a href="#7" class="mim-tip-reference" title="Morin, R. D., Mendez-Lago, M., Mungall, A. J., Goya, R., Mungall, K. L., Corbett, R. D., Johnson, N. A., Severson, T. M., Chiu, R., Field, M., Jackman, S., Krzywinski, M., and 38 others. <strong>Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma.</strong> Nature 476: 298-303, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21796119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21796119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21796119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21796119">Morin et al. (2011)</a> observed enrichment for nonsense mutations in BCL10 (<a href="/entry/603517">603517</a>), a positive regulator of NF-kappa-B in which oncogenic truncated products have been described in lymphomas. The remaining strongly significant genes (BTG1, <a href="/entry/109580">109580</a>; GNA13, <a href="/entry/604406">604406</a>; SGK1, <a href="/entry/602958">602958</a>; and MLL2, <a href="/entry/602113">602113</a>) had no reported role in lymphoma. GNA13 encodes the alpha subunit of a heterotrimeric G protein-coupled receptor responsible for modulating RhoA activity. SGK1 encodes a phosphatidylinositol-3-hydroxy kinase-regulated kinase with functions including regulation of FOXO transcription factors, regulation of NF-kappa-B by phosphorylating I-kappa-B kinase (see <a href="/entry/600664">600664</a>), and negative regulation of NOTCH (<a href="/entry/190198">190198</a>) signaling. SGK1 also resides within a region of chromosome 6 commonly deleted in DLBCL. Both SGK1 and GNA13 mutations were found only in germinal center B-cell lymphomas. MEF2B and TNFRSF14, which had no previously described role in DLBCL, were similarly restricted to germinal center B-cell lymphomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21796119" 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 identify tumor suppressor genes in lymphoma, <a href="#9" class="mim-tip-reference" title="Scuoppo, C., Miething, C., Lindqvist, L., Reyes, J., Ruse, C., Appelmann, I., Yoon, S., Krasnitz, A., Teruya-Feldstein, J., Pappin, D., Pelletier, J., Lowe, S. W. <strong>A tumour suppressor network relying on the polyamine-hypusine axis.</strong> Nature 487: 244-248, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722845</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722845[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22722845">Scuoppo et al. (2012)</a> screened a short hairpin RNA library targeting genes deleted in human lymphomas and functionally confirmed those in a mouse lymphoma model. Of the 9 tumor suppressors identified, 8 corresponded to genes occurring in 3 physically linked 'clusters,' suggesting that the common occurrence of large chromosomal deletions in human tumors reflects selective pressure to attenuate multiple genes. Among the new tumor suppressors are adenosylmethionine decarboxylase-1 (AMD1; <a href="/entry/180980">180980</a>) and eukaryotic translation initiation factor 5A (eIF5A; <a href="/entry/600187">600187</a>), 2 genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, <a href="#9" class="mim-tip-reference" title="Scuoppo, C., Miething, C., Lindqvist, L., Reyes, J., Ruse, C., Appelmann, I., Yoon, S., Krasnitz, A., Teruya-Feldstein, J., Pappin, D., Pelletier, J., Lowe, S. W. <strong>A tumour suppressor network relying on the polyamine-hypusine axis.</strong> Nature 487: 244-248, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722845</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722845[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22722845">Scuoppo et al. (2012)</a> established the polyamine-hypusine axis as a new tumor suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas, and cosuppression of both genes promotes lymphomagenesis in mice. Thus, <a href="#9" class="mim-tip-reference" title="Scuoppo, C., Miething, C., Lindqvist, L., Reyes, J., Ruse, C., Appelmann, I., Yoon, S., Krasnitz, A., Teruya-Feldstein, J., Pappin, D., Pelletier, J., Lowe, S. W. <strong>A tumour suppressor network relying on the polyamine-hypusine axis.</strong> Nature 487: 244-248, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722845</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722845[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22722845">Scuoppo et al. (2012)</a> concluded that some tumor suppressor functions can be disabled through a 2-step process targeting different genes acting in the same pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22722845" 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>REFERENCES</strong>
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<a id="Altieri2005" class="mim-anchor"></a>
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<p class="mim-text-font">
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Altieri, A., Bermejo, J. L., Hemminki, K.
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<strong>Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database.</strong>
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Blood 106: 668-672, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15811955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15811955</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15811955" 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/10.1182/blood-2005-01-0140" target="_blank">Full Text</a>]
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<a id="Clementi2005" class="mim-anchor"></a>
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Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G.
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<strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong>
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Blood 105: 4424-4428, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728124</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15728124" 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/10.1182/blood-2004-04-1477" target="_blank">Full Text</a>]
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<a id="Compagno2009" class="mim-anchor"></a>
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<p class="mim-text-font">
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Compagno, M., Lim, W. K., Grunn, A., Nandula, S. V., Brahmachary, M., Shen, Q., Bertoni, F., Ponzoni, M., Scandurra, M., Califano, A., Bhagat, G., Chadburn, A., Dalla-Favera, R., Pasqualucci, L.
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<strong>Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.</strong>
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Nature 459: 717-721, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412164[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=19412164" 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/nature07968" target="_blank">Full Text</a>]
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<a id="Davis2010" class="mim-anchor"></a>
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Davis, R. E., Ngo, V. N., Lenz, G., Tolar, P., Young, R. M., Romesser, P. B., Kohlhammer, H., Lamy, L., Zhao, H., Yang, Y., Xu, W., Shaffer, A. L., and 25 others.
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<strong>Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.</strong>
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Nature 463: 88-92, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20054396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20054396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20054396[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=20054396" 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/nature08638" target="_blank">Full Text</a>]
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<a id="Lenz2008" class="mim-anchor"></a>
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Lenz, G., Davis, R. E., Ngo, V. N., Lam, L., George, T. C., Wright, G. W., Dave, S. S., Zhao, H., Xu, W., Rosenwald, A., Ott, G., Muller-Hermelink, H. K., and 10 others.
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<strong>Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.</strong>
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Science 319: 1676-1679, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18323416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18323416</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18323416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1153629" target="_blank">Full Text</a>]
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Morin, R. D., Johnson, N. A., Severson, T. M., Mungall, A. J., An, J., Goya, R., Paul, J. E., Boyle, M., Woolcock, B. W., Kuchenbauer, F., Yap, D., Humphries, R. K., and 26 others.
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<strong>Somatic mutations altering EZH2 (tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.</strong>
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Nature Genet. 42: 181-185, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20081860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20081860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20081860[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=20081860" 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.518" target="_blank">Full Text</a>]
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</p>
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<a id="7" class="mim-anchor"></a>
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<a id="Morin2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Morin, R. D., Mendez-Lago, M., Mungall, A. J., Goya, R., Mungall, K. L., Corbett, R. D., Johnson, N. A., Severson, T. M., Chiu, R., Field, M., Jackman, S., Krzywinski, M., and 38 others.
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<strong>Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma.</strong>
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Nature 476: 298-303, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21796119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21796119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21796119[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=21796119" 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/nature10351" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Pasqualucci2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pasqualucci, L., Dominguez-Sola, D., Chiarenza, A., Fabbri, G., Grunn, A., Trifonov, V., Kasper, L. H., Lerach, S., Tang, H., Ma, J., Rossi, D., Chadburn, A., Murty, V. V., Mullighan, C. G., Gaidano, G., Rabadan, R., Brindle, P. K., Dalla-Favera, R.
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<strong>Inactivating mutations of acetyltransferase genes in B-cell lymphoma.</strong>
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Nature 471: 189-195, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21390126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21390126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21390126[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=21390126" 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/nature09730" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Scuoppo2012" class="mim-anchor"></a>
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Scuoppo, C., Miething, C., Lindqvist, L., Reyes, J., Ruse, C., Appelmann, I., Yoon, S., Krasnitz, A., Teruya-Feldstein, J., Pappin, D., Pelletier, J., Lowe, S. W.
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<strong>A tumour suppressor network relying on the polyamine-hypusine axis.</strong>
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Nature 487: 244-248, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22722845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22722845</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22722845[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=22722845" 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/nature11126" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Wiernik2000" class="mim-anchor"></a>
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<div class="">
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Wiernik, P. H., Wang, S. Q., Hu, X.-P., Marino, P., Paietta, E.
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<strong>Age of onset evidence for anticipation in familial non-Hodgkin's lymphoma.</strong>
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Brit. J. Haemat. 108: 72-79, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10651726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10651726</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10651726" 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/10.1046/j.1365-2141.2000.01815.x" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 8/29/2012
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Marla J. F. O'Neill - updated : 1/10/2012<br>Ada Hamosh - updated : 9/6/2011<br>Ada Hamosh - updated : 6/14/2011<br>Ada Hamosh - updated : 2/2/2010<br>Ada Hamosh - updated : 6/16/2009<br>Ada Hamosh - updated : 5/21/2008<br>Marla J. F. O'Neill - updated : 10/6/2005<br>Victor A. McKusick - updated : 1/20/2004<br>Victor A. McKusick - updated : 8/23/2002
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Victor A. McKusick : 6/1/2000
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carol : 08/21/2019
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carol : 08/21/2019<br>carol : 05/31/2018<br>joanna : 06/24/2016<br>alopez : 9/4/2012<br>terry : 8/29/2012<br>carol : 1/10/2012<br>alopez : 9/7/2011<br>terry : 9/6/2011<br>terry : 9/6/2011<br>alopez : 6/16/2011<br>alopez : 6/16/2011<br>terry : 6/14/2011<br>alopez : 2/22/2010<br>terry : 2/2/2010<br>alopez : 6/17/2009<br>terry : 6/16/2009<br>joanna : 4/16/2009<br>alopez : 5/21/2008<br>alopez : 5/21/2008<br>carol : 2/15/2008<br>wwang : 11/15/2005<br>ckniffin : 10/17/2005<br>wwang : 10/14/2005<br>terry : 10/6/2005<br>cwells : 1/22/2004<br>terry : 1/20/2004<br>ckniffin : 3/11/2003<br>mgross : 9/10/2002<br>tkritzer : 9/10/2002<br>terry : 8/23/2002<br>mgross : 6/1/2000
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<strong>#</strong> 605027
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LYMPHOMA, NON-HODGKIN, FAMILIAL
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<span class="mim-font">
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NON-HODGKIN LYMPHOMA; NHL
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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-text-font">
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<strong>ORPHA:</strong> 547;
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<strong>DO:</strong> 0060060;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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|
Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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|
Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
|
1p34.1
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|
</span>
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</td>
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<td>
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<span class="mim-font">
|
|
Lymphoma, non-Hodgkin, somatic
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|
</span>
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</td>
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<td>
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|
<span class="mim-font">
|
|
605027
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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|
<span class="mim-font">
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3
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</span>
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</td>
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<td>
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|
<span class="mim-font">
|
|
RAD54L
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</span>
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</td>
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<td>
|
|
<span class="mim-font">
|
|
603615
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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1p22.3
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
{Lymphoma, follicular, somatic}
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|
</span>
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</td>
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<td>
|
|
<span class="mim-font">
|
|
605027
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|
</span>
|
|
</td>
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<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
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</td>
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
BCL10
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
603517
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
2q33.1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Lymphoma, non-Hodgkin, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
605027
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
CASP10
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
601762
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
8q22.1
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|
</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Lymphoma, non-Hodgkin, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
605027
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
RAD54B
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
604289
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
10q22.1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Lymphoma, non-Hodgkin
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
605027
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
PRF1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
170280
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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|
|
<div>
|
|
<br />
|
|
</div>
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|
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|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>A number sign (#) is used with this entry because non-Hodgkin lymphoma is associated with somatic mutations in a number of genes, including CASP10 (601762), ATM (607585), RAD54L (603615), BRAF (164757), CARD11 (607210), and RAD54B (604289).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Inheritance</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Wiernik et al. (2000) analyzed 11 published reports of multigenerational familial non-Hodgkin lymphoma (NHL) and 18 previously unreported families with familial NHL for evidence of anticipation. They determined the difference in disease-free survival between generations and the difference in the age of onset for each affected parent-child pair. To avoid ascertainment bias, the analyses were also performed separately using only parent-child pairs with age of onset greater than 25 years. In addition, the age-of-onset distribution of the studied cases was compared with that of the Surveillance Epidemiology and End Results (SEER) program using data for 1973 to 1998. The median age of onset in the child and parent generations of all families (48.5 and 78.3 years, respectively) and in the selected pairs (52.5 and 71.5 years, respectively) was significantly different. A significant difference was observed between the ages of onset between the child generation and that of the SEER population but not between the parent generation and the SEER population. Wiernik et al. (2000) concluded that anticipation in familial NHL is a genuine phenomenon and suggests a genetic role in the disorder. </p><p>Using the Swedish Family-Cancer Database, Altieri et al. (2005) calculated standardized incidence ratios (SIRs) for histopathology-specific subtypes of NHL in 4,455 offspring with NHL whose parents or sibs were affected with different types of lymphoproliferative malignancies. SIRs for affected patients with a parental history of NHL were significantly increased for NHL (1.8) and diffuse large B-cell lymphoma (2.3). SIRs for affected patients with a sib history of NHL were significantly increased for NHL (1.9), follicular lymphoma (2.3), and B-cell lymphoma not otherwise specified (3.4). With a parental history of histopathology-specific concordant cancer, familial risks were significantly increased for diffuse large B-cell lymphoma, follicular NHL, plasma cell myeloma, and chronic lymphocytic leukemia (SIRs of 11.8, 6.1, 2.5, and 5.9, respectively). Altieri et al. (2005) concluded that there is a strong familial association in NHL. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Pathogenesis</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Roughly 10% of activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCLs) have mutant CARD11 (607210) isoforms that activate NF-kappa-B (see 164011). Davis et al. (2010) used an RNA interference genetic screen to show that the BCR signaling component Bruton tyrosine kinase (BTK; 300300) is essential for the survival of ABC DLBCLs with wildtype CARD11. In addition, knockdown of proximal BCR subunits (IgM, see 147020; Ig-kappa, see 147200; CD79A, 112205; and CD79B, 147245) killed ABC DLBCLs with wildtype CARD11 but not other lymphomas. The B cell receptors in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signaling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine at position 196, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase (165120), a feedback inhibitor of BCR signaling. Davis et al. (2010) concluded that their findings establish chronic active BCR signaling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Clementi et al. (2005) reported 4 patients with non-Hodgkin lymphoma with features of hemophagocytic lymphohistiocytosis (603533) who had mutations in the perforin gene (see 170280.0002; 170280.0009; 170280.0011). </p><p>DLBCL is the most common form of non-Hodgkin lymphoma, accounting for 30 to 40% of cases (Lenz et al., 2008). DLBCL consists of 3 subtypes: germinal center B cell-like (GCB) DLBCL, ABC DLBCL, and primary mediastinal B cell lymphoma. The ABC DLBCL subtype accounts for roughly one-third of the cases and has an inferior prognosis. A characteristic feature of ABC DLBCL is constitutive activation of the NF-kappa-B (see 164011) pathway, which plays a pivotal role in proliferation, differentiation, and survival of normal lymphoid cells. In normal B cells, antigen receptor-induced NF-kappa-B activation requires CARD11 (607210), a cytoplasmic scaffolding protein. To determine whether CARD11 contributes to tumorigenesis, Lenz et al. (2008) sequenced the CARD11 gene in human DLBCL tumors. Lenz et al. (2008) detected missense mutations in 7 of 73 ABC DLBCL biopsies (9.6%), all within exons encoding the coiled-coil domain. Experimental introduction of CARD11 coiled-coil domain mutants into lymphoma cell lines resulted in constitutive NF-kappa-B activation and enhanced the NF-kappa-B activity upon antigen receptor stimulation. Lenz et al. (2008) concluded that CARD11 is a bona fide oncogene in DLBCL. </p><p>Compagno et al. (2009) showed that greater than 50% of ABC DLBCL and a smaller fraction of germinal center B cell-like (GCB) DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3; 191163) and positive (including CARD11 and TRAF2, 601895) regulators of NF-kappa-B. Of these, the TNFAIP3 gene, which encodes a ubiquitin-modifying enzyme (A20) involved in termination of NF-kappa-B responses, is most commonly affected, with approximately 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumor suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kappa-B. Compagno et al. (2009) concluded that NF-kappa-B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappa-B responses. </p><p>Morin et al. (2010) identified recurrent somatic mutations affecting the tyr641 residue of the conserved SET domain in the EZH2 gene (601573) in cases of follicular lymphoma and diffuse large B-cell lymphoma of only the GCB subtype. Their data indicated that mutation involving this tyrosine was among the most frequent genetic events observed in GCB malignancies, after t(14;18)(q32;q21) translocations. </p><p>Pasqualucci et al. (2011) reported that the 2 most common types of B cell non-Hodgkin lymphoma, follicular lymphoma and diffuse large B-cell lymphoma, harbor frequent structural alterations inactivating CREBBP (600140) and, more rarely, EP300 (602700), 2 highly related histone and nonhistone acetyltransferases (HATs) that act as transcriptional coactivators in multiple signaling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these 2 genes. These lesions usually affect 1 allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. Pasqualucci et al. (2011) demonstrated specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein (109565) and activation of the p53 tumor suppressor (191170). </p><p>Morin et al. (2011) sequenced tumor and matched control DNA from 13 DLBCL cases and 1 follicular lymphoma case to identify genes with mutations in B-cell NHL. Morin et al. (2011) analyzed RNA sequencing data from these and another 113 NHLs to identify genes with candidate mutations, and then resequenced tumor and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of follicular lymphoma cases had somatic mutations in MLL2 (602113), which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and follicular lymphoma cases, respectively, had mutations in MEF2B (601661), a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Morin et al. (2011) concluded that their analysis suggested a previously unappreciated disruption of chromatin biology in lymphomagenesis. In their analysis, Morin et al. (2011) found that the 8 most significant genes included 7 with strong selective pressure for nonsense mutations, including the known tumor suppressor genes TP53 and TNFRSF14 (602746). CREBBP also showed some evidence for acquisition of nonsense mutations and coding single-nucleotide variants. Morin et al. (2011) observed enrichment for nonsense mutations in BCL10 (603517), a positive regulator of NF-kappa-B in which oncogenic truncated products have been described in lymphomas. The remaining strongly significant genes (BTG1, 109580; GNA13, 604406; SGK1, 602958; and MLL2, 602113) had no reported role in lymphoma. GNA13 encodes the alpha subunit of a heterotrimeric G protein-coupled receptor responsible for modulating RhoA activity. SGK1 encodes a phosphatidylinositol-3-hydroxy kinase-regulated kinase with functions including regulation of FOXO transcription factors, regulation of NF-kappa-B by phosphorylating I-kappa-B kinase (see 600664), and negative regulation of NOTCH (190198) signaling. SGK1 also resides within a region of chromosome 6 commonly deleted in DLBCL. Both SGK1 and GNA13 mutations were found only in germinal center B-cell lymphomas. MEF2B and TNFRSF14, which had no previously described role in DLBCL, were similarly restricted to germinal center B-cell lymphomas. </p><p>To identify tumor suppressor genes in lymphoma, Scuoppo et al. (2012) screened a short hairpin RNA library targeting genes deleted in human lymphomas and functionally confirmed those in a mouse lymphoma model. Of the 9 tumor suppressors identified, 8 corresponded to genes occurring in 3 physically linked 'clusters,' suggesting that the common occurrence of large chromosomal deletions in human tumors reflects selective pressure to attenuate multiple genes. Among the new tumor suppressors are adenosylmethionine decarboxylase-1 (AMD1; 180980) and eukaryotic translation initiation factor 5A (eIF5A; 600187), 2 genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, Scuoppo et al. (2012) established the polyamine-hypusine axis as a new tumor suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas, and cosuppression of both genes promotes lymphomagenesis in mice. Thus, Scuoppo et al. (2012) concluded that some tumor suppressor functions can be disabled through a 2-step process targeting different genes acting in the same pathway. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Altieri, A., Bermejo, J. L., Hemminki, K.
|
|
<strong>Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database.</strong>
|
|
Blood 106: 668-672, 2005.
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|
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|
|
[PubMed: 15811955]
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[Full Text: https://doi.org/10.1182/blood-2005-01-0140]
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</p>
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|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G.
|
|
<strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong>
|
|
Blood 105: 4424-4428, 2005.
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|
|
[PubMed: 15728124]
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[Full Text: https://doi.org/10.1182/blood-2004-04-1477]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Compagno, M., Lim, W. K., Grunn, A., Nandula, S. V., Brahmachary, M., Shen, Q., Bertoni, F., Ponzoni, M., Scandurra, M., Califano, A., Bhagat, G., Chadburn, A., Dalla-Favera, R., Pasqualucci, L.
|
|
<strong>Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.</strong>
|
|
Nature 459: 717-721, 2009.
|
|
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|
|
[PubMed: 19412164]
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[Full Text: https://doi.org/10.1038/nature07968]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Davis, R. E., Ngo, V. N., Lenz, G., Tolar, P., Young, R. M., Romesser, P. B., Kohlhammer, H., Lamy, L., Zhao, H., Yang, Y., Xu, W., Shaffer, A. L., and 25 others.
|
|
<strong>Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.</strong>
|
|
Nature 463: 88-92, 2010.
|
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|
|
[PubMed: 20054396]
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[Full Text: https://doi.org/10.1038/nature08638]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lenz, G., Davis, R. E., Ngo, V. N., Lam, L., George, T. C., Wright, G. W., Dave, S. S., Zhao, H., Xu, W., Rosenwald, A., Ott, G., Muller-Hermelink, H. K., and 10 others.
|
|
<strong>Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.</strong>
|
|
Science 319: 1676-1679, 2008.
|
|
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|
|
[PubMed: 18323416]
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|
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Morin, R. D., Mendez-Lago, M., Mungall, A. J., Goya, R., Mungall, K. L., Corbett, R. D., Johnson, N. A., Severson, T. M., Chiu, R., Field, M., Jackman, S., Krzywinski, M., and 38 others.
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