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Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing.


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.

SUBMITTER: Lohr JG 

PROVIDER: S-EPMC3309757 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing.

Lohr Jens G JG   Stojanov Petar P   Lawrence Michael S MS   Auclair Daniel D   Chapuy Bjoern B   Sougnez Carrie C   Cruz-Gordillo Peter P   Knoechel Birgit B   Asmann Yan W YW   Slager Susan L SL   Novak Anne J AJ   Dogan Ahmet A   Ansell Stephen M SM   Link Brian K BK   Zou Lihua L   Gould Joshua J   Saksena Gordon G   Stransky Nicolas N   Rangel-Escareño Claudia C   Fernandez-Lopez Juan Carlos JC   Hidalgo-Miranda Alfredo A   Melendez-Zajgla Jorge J   Hernández-Lemus Enrique E   Schwarz-Cruz y Celis Angela A   Imaz-Rosshandler Ivan I   Ojesina Akinyemi I AI   Jung Joonil J   Pedamallu Chandra S CS   Lander Eric S ES   Habermann Thomas M TM   Cerhan James R JR   Shipp Margaret A MA   Getz Gad G   Golub Todd R TR  

Proceedings of the National Academy of Sciences of the United States of America 20120217 10


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 ME  ...[more]

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