TY - JOUR
T1 - Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing
AU - Lohr, Jens G.
AU - Stojanov, Petar
AU - Lawrence, Michael S.
AU - Auclair, Daniel
AU - Chapuy, Bjoern
AU - Sougnez, Carrie
AU - Cruz-Gordillo, Peter
AU - Knoechel, Birgit
AU - Asmann, Yan W.
AU - Slager, Susan L.
AU - Novak, Anne J.
AU - Dogan, Ahmet
AU - Ansell, Stephen M.
AU - Link, Brian K.
AU - Zou, Lihua
AU - Gould, Joshua
AU - Saksena, Gordon
AU - Stransky, Nicolas
AU - Rangel-Escareño, Claudia
AU - Fernandez-Lopez, Juan Carlos
AU - Hidalgo-Miranda, Alfredo
AU - Melendez-Zajgla, Jorge
AU - Hernández-Lemus, Enrique
AU - Schwarz-Cruz y Celis, Angela
AU - Imaz-Rosshandler, Ivan
AU - Ojesina, Akinyemi I.
AU - Jung, Joonil
AU - Pedamallu, Chandra S.
AU - Lander, Eric S.
AU - Habermann, Thomas M.
AU - Cerhan, James R.
AU - Shipp, Margaret A.
AU - Getz, Gad
AU - Golub, Todd R.
PY - 2012/3/6
Y1 - 2012/3/6
N2 - 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.
AB - 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.
KW - Activation-induced deaminase
KW - Human genetics
KW - Next-generation sequencing
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UR - http://www.scopus.com/inward/citedby.url?scp=84857942952&partnerID=8YFLogxK
U2 - 10.1073/pnas.1121343109
DO - 10.1073/pnas.1121343109
M3 - Article
C2 - 22343534
AN - SCOPUS:84857942952
SN - 0027-8424
VL - 109
SP - 3879
EP - 3884
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -