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

Jens G. Lohr, Petar Stojanov, Michael S. Lawrence, Daniel Auclair, Bjoern Chapuy, Carrie Sougnez, Peter Cruz-Gordillo, Birgit Knoechel, Yan W. Asmann, Susan L. Slager, Anne J. Novak, Ahmet Dogan, Stephen M. Ansell, Brian K. Link, Lihua Zou, Joshua Gould, Gordon Saksena, Nicolas Stransky, Claudia Rangel-Escareño, Juan Carlos Fernandez-LopezAlfredo Hidalgo-Miranda, Jorge Melendez-Zajgla, Enrique Hernández-Lemus, Angela Schwarz-Cruz y Celis, Ivan Imaz-Rosshandler, Akinyemi I. Ojesina, Joonil Jung, Chandra S. Pedamallu, Eric S. Lander, Thomas M. Habermann, James R. Cerhan, Margaret A. Shipp, Gad Getz, Todd R. Golub

Research output: Contribution to journalArticlepeer-review

673 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3879-3884
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number10
StatePublished - Mar 6 2012


  • Activation-induced deaminase
  • Human genetics
  • Next-generation sequencing

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing'. Together they form a unique fingerprint.

Cite this