Journal article
Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing
Proceedings of the National Academy of Sciences - PNAS, Vol.109(10), pp.3879-3884
03/06/2012
DOI: 10.1073/pnas.1121343109
PMCID: PMC3309757
PMID: 22343534
Abstract
To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase–mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease.
Details
- Title: Subtitle
- Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing
- Creators
- Ahmet Dogan - , RochesterBrian K Link - , Iowa CityJens G Lohr - , CambridgeJames R Cerhan - , RochesterPetar Stojanov - , CambridgeMichael S Lawrence - , CambridgeDaniel Auclair - , CambridgeBjoern Chapuy - , BostonCarrie Sougnez - , CambridgePeter Cruz-Gordillo - , CambridgeBirgit Knoechel - , CambridgeYan W Asmann - , RochesterSusan L Slager - , RochesterAnne J Novak - , RochesterStephen M Ansell - , RochesterLihua Zou - , CambridgeJoshua Gould - , CambridgeGordon Saksena - , CambridgeNicolas Stransky - , CambridgeJuan Carlos Fernandez-Lopez - , 14610 Mexico DFClaudia Rangel-Escareño - , 14610 Mexico DFAlfredo Hidalgo-Miranda - , 14610 Mexico DFJorge Melendez-Zajgla - , 14610 Mexico DFEnrique Hernández-Lemus - , 14610 Mexico DFAngela Schwarz-Cruz y Celis - , 14610 Mexico DFIvan Imaz-Rosshandler - , 14610 Mexico DFAkinyemi I Ojesina - , CambridgeJoonil Jung - , CambridgeChandra S Pedamallu - , CambridgeEric S Lander - , CambridgeThomas M Habermann - , RochesterMargaret A Shipp - , BostonGad Getz - , CambridgeTodd R Golub - , Cambridge
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.109(10), pp.3879-3884
- DOI
- 10.1073/pnas.1121343109
- PMID
- 22343534
- PMCID
- PMC3309757
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 03/06/2012
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Internal Medicine
- Record Identifier
- 9984094525002771
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