Landscape of somatic mutations and clonal evolution in mantle cell lymphoma
Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA,...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2013-11, Vol.110 (45), p.18250-18255 |
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| creator | Beà, Sílvia Valdés-Mas, Rafael Navarro, Alba Salaverria, Itziar Martín-Garcia, David Jares, Pedro Giné, Eva Pinyol, Magda Royo, Cristina Nadeu, Ferran Conde, Laura Juan, Manel Clot, Guillem Vizán, Pedro Di Croce, Luciano Puente, Diana A. López-Guerra, Mónica Moros, Alexandra Roue, Gael Aymerich, Marta Villamor, Neus Colomo, Lluís Martínez, Antonio Valera, Alexandra Martín-Subero, José I. Amador, Virginia Hernández, Luis Rozman, Maria Enjuanes, Anna Forcada, Pilar Muntañola, Ana Hartmann, Elena M. Calasanz, María J. Rosenwald, Andreas Ott, German Hernández-Rivas, Jesús M. Klapper, Wolfram Siebert, Reiner Wiestner, Adrian Wilson, Wyndham H. Colomer, Dolors López-Guillermo, Armando López-Otín, Carlos Puente, Xose S. Campo, Elías |
| description | Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53 ; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1 , MLL2 , and MEF2B . We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention. |
| doi_str_mv | 10.1073/pnas.1314608110 |
| format | Article |
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To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53 ; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1 , MLL2 , and MEF2B . We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1314608110</identifier><identifier>PMID: 24145436</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Ataxia Telangiectasia Mutated Proteins - genetics ; Base Sequence ; Biological Sciences ; Blood ; Cell lines ; Chromatin ; Clonal Evolution - genetics ; Cloning ; Cyclin D1 - genetics ; cyclins ; disease course ; DNA ; Evolution ; Genes ; Genetic mutation ; Genetic Variation ; Genome, Human - genetics ; Genome-Wide Association Study ; Genomics - methods ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; Lymphoma ; Lymphoma, Mantle-Cell - genetics ; Lymphoma, Mantle-Cell - physiopathology ; Mantle cell lymphoma ; Medical diagnosis ; Microarray Analysis ; Molecular Sequence Data ; Mutation ; Mutation - genetics ; neoplasm cells ; neoplasms ; Pathogenesis ; patients ; pro-apoptotic proteins ; prognosis ; Receptor, Notch2 - genetics ; Sequencing ; Somatic mutation ; T cell receptors ; Toll-like receptor 2 ; Toll-Like Receptor 2 - genetics ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2013-11, Vol.110 (45), p.18250-18255</ispartof><rights>copyright © 1993–2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Nov 5, 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c624t-607327c21a7714b2fd52ffc60ec76ab58d7e02554feaee85ccdc3454abb93283</citedby><cites>FETCH-LOGICAL-c624t-607327c21a7714b2fd52ffc60ec76ab58d7e02554feaee85ccdc3454abb93283</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/110/45.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/23754766$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/23754766$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27903,27904,53769,53771,57995,58228</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24145436$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Beà, Sílvia</creatorcontrib><creatorcontrib>Valdés-Mas, Rafael</creatorcontrib><creatorcontrib>Navarro, Alba</creatorcontrib><creatorcontrib>Salaverria, Itziar</creatorcontrib><creatorcontrib>Martín-Garcia, David</creatorcontrib><creatorcontrib>Jares, Pedro</creatorcontrib><creatorcontrib>Giné, Eva</creatorcontrib><creatorcontrib>Pinyol, Magda</creatorcontrib><creatorcontrib>Royo, Cristina</creatorcontrib><creatorcontrib>Nadeu, Ferran</creatorcontrib><creatorcontrib>Conde, Laura</creatorcontrib><creatorcontrib>Juan, Manel</creatorcontrib><creatorcontrib>Clot, Guillem</creatorcontrib><creatorcontrib>Vizán, Pedro</creatorcontrib><creatorcontrib>Di Croce, Luciano</creatorcontrib><creatorcontrib>Puente, Diana A.</creatorcontrib><creatorcontrib>López-Guerra, Mónica</creatorcontrib><creatorcontrib>Moros, Alexandra</creatorcontrib><creatorcontrib>Roue, Gael</creatorcontrib><creatorcontrib>Aymerich, Marta</creatorcontrib><creatorcontrib>Villamor, Neus</creatorcontrib><creatorcontrib>Colomo, Lluís</creatorcontrib><creatorcontrib>Martínez, Antonio</creatorcontrib><creatorcontrib>Valera, Alexandra</creatorcontrib><creatorcontrib>Martín-Subero, José I.</creatorcontrib><creatorcontrib>Amador, Virginia</creatorcontrib><creatorcontrib>Hernández, Luis</creatorcontrib><creatorcontrib>Rozman, Maria</creatorcontrib><creatorcontrib>Enjuanes, Anna</creatorcontrib><creatorcontrib>Forcada, Pilar</creatorcontrib><creatorcontrib>Muntañola, Ana</creatorcontrib><creatorcontrib>Hartmann, Elena M.</creatorcontrib><creatorcontrib>Calasanz, María J.</creatorcontrib><creatorcontrib>Rosenwald, Andreas</creatorcontrib><creatorcontrib>Ott, German</creatorcontrib><creatorcontrib>Hernández-Rivas, Jesús M.</creatorcontrib><creatorcontrib>Klapper, Wolfram</creatorcontrib><creatorcontrib>Siebert, Reiner</creatorcontrib><creatorcontrib>Wiestner, Adrian</creatorcontrib><creatorcontrib>Wilson, Wyndham H.</creatorcontrib><creatorcontrib>Colomer, Dolors</creatorcontrib><creatorcontrib>López-Guillermo, Armando</creatorcontrib><creatorcontrib>López-Otín, Carlos</creatorcontrib><creatorcontrib>Puente, Xose S.</creatorcontrib><creatorcontrib>Campo, Elías</creatorcontrib><title>Landscape of somatic mutations and clonal evolution in mantle cell lymphoma</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53 ; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1 , MLL2 , and MEF2B . We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.</description><subject>Ataxia Telangiectasia Mutated Proteins - genetics</subject><subject>Base Sequence</subject><subject>Biological Sciences</subject><subject>Blood</subject><subject>Cell lines</subject><subject>Chromatin</subject><subject>Clonal Evolution - genetics</subject><subject>Cloning</subject><subject>Cyclin D1 - genetics</subject><subject>cyclins</subject><subject>disease course</subject><subject>DNA</subject><subject>Evolution</subject><subject>Genes</subject><subject>Genetic mutation</subject><subject>Genetic Variation</subject><subject>Genome, Human - genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genomics - methods</subject><subject>Genotype</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Humans</subject><subject>Lymphoma</subject><subject>Lymphoma, Mantle-Cell - genetics</subject><subject>Lymphoma, Mantle-Cell - physiopathology</subject><subject>Mantle cell lymphoma</subject><subject>Medical diagnosis</subject><subject>Microarray Analysis</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>neoplasm cells</subject><subject>neoplasms</subject><subject>Pathogenesis</subject><subject>patients</subject><subject>pro-apoptotic proteins</subject><subject>prognosis</subject><subject>Receptor, Notch2 - genetics</subject><subject>Sequencing</subject><subject>Somatic mutation</subject><subject>T cell receptors</subject><subject>Toll-like receptor 2</subject><subject>Toll-Like Receptor 2 - 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Andreas</creatorcontrib><creatorcontrib>Ott, German</creatorcontrib><creatorcontrib>Hernández-Rivas, Jesús M.</creatorcontrib><creatorcontrib>Klapper, Wolfram</creatorcontrib><creatorcontrib>Siebert, Reiner</creatorcontrib><creatorcontrib>Wiestner, Adrian</creatorcontrib><creatorcontrib>Wilson, Wyndham H.</creatorcontrib><creatorcontrib>Colomer, Dolors</creatorcontrib><creatorcontrib>López-Guillermo, Armando</creatorcontrib><creatorcontrib>López-Otín, Carlos</creatorcontrib><creatorcontrib>Puente, Xose S.</creatorcontrib><creatorcontrib>Campo, Elías</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Beà, Sílvia</au><au>Valdés-Mas, Rafael</au><au>Navarro, Alba</au><au>Salaverria, Itziar</au><au>Martín-Garcia, David</au><au>Jares, Pedro</au><au>Giné, Eva</au><au>Pinyol, Magda</au><au>Royo, Cristina</au><au>Nadeu, Ferran</au><au>Conde, Laura</au><au>Juan, Manel</au><au>Clot, Guillem</au><au>Vizán, Pedro</au><au>Di Croce, Luciano</au><au>Puente, Diana A.</au><au>López-Guerra, Mónica</au><au>Moros, Alexandra</au><au>Roue, Gael</au><au>Aymerich, Marta</au><au>Villamor, Neus</au><au>Colomo, Lluís</au><au>Martínez, Antonio</au><au>Valera, Alexandra</au><au>Martín-Subero, José I.</au><au>Amador, Virginia</au><au>Hernández, Luis</au><au>Rozman, Maria</au><au>Enjuanes, Anna</au><au>Forcada, Pilar</au><au>Muntañola, Ana</au><au>Hartmann, Elena M.</au><au>Calasanz, María J.</au><au>Rosenwald, Andreas</au><au>Ott, German</au><au>Hernández-Rivas, Jesús M.</au><au>Klapper, Wolfram</au><au>Siebert, Reiner</au><au>Wiestner, Adrian</au><au>Wilson, Wyndham H.</au><au>Colomer, Dolors</au><au>López-Guillermo, Armando</au><au>López-Otín, Carlos</au><au>Puente, Xose S.</au><au>Campo, Elías</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Landscape of somatic mutations and clonal evolution in mantle cell lymphoma</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2013-11-05</date><risdate>2013</risdate><volume>110</volume><issue>45</issue><spage>18250</spage><epage>18255</epage><pages>18250-18255</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53 ; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1 , MLL2 , and MEF2B . We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>24145436</pmid><doi>10.1073/pnas.1314608110</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2013-11, Vol.110 (45), p.18250-18255 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_proquest_journals_1458347862 |
| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Ataxia Telangiectasia Mutated Proteins - genetics Base Sequence Biological Sciences Blood Cell lines Chromatin Clonal Evolution - genetics Cloning Cyclin D1 - genetics cyclins disease course DNA Evolution Genes Genetic mutation Genetic Variation Genome, Human - genetics Genome-Wide Association Study Genomics - methods Genotype High-Throughput Nucleotide Sequencing Humans Lymphoma Lymphoma, Mantle-Cell - genetics Lymphoma, Mantle-Cell - physiopathology Mantle cell lymphoma Medical diagnosis Microarray Analysis Molecular Sequence Data Mutation Mutation - genetics neoplasm cells neoplasms Pathogenesis patients pro-apoptotic proteins prognosis Receptor, Notch2 - genetics Sequencing Somatic mutation T cell receptors Toll-like receptor 2 Toll-Like Receptor 2 - genetics Tumors |
| title | Landscape of somatic mutations and clonal evolution in mantle cell lymphoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T04%3A27%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Landscape%20of%20somatic%20mutations%20and%20clonal%20evolution%20in%20mantle%20cell%20lymphoma&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Be%C3%A0,%20S%C3%ADlvia&rft.date=2013-11-05&rft.volume=110&rft.issue=45&rft.spage=18250&rft.epage=18255&rft.pages=18250-18255&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.1314608110&rft_dat=%3Cjstor_proqu%3E23754766%3C/jstor_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1458347862&rft_id=info:pmid/24145436&rft_jstor_id=23754766&rfr_iscdi=true |