title: 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.
authors.affiliation: Eli and Edythe Broad Institute, Cambridge, MA 02412, USA.
authors.forename: Jens G
authors.initials: JG
authors.lastname: Lohr
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Daniel
authors.initials: D
authors.lastname: Auclair
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.forename: Peter
authors.initials: P
authors.lastname: Cruz-Gordillo
authors.forename: Birgit
authors.initials: B
authors.lastname: Knoechel
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Brian K
authors.initials: BK
authors.lastname: Link
authors.forename: Lihua
authors.initials: L
authors.lastname: Zou
authors.forename: Joshua
authors.initials: J
authors.lastname: Gould
authors.forename: Gordon
authors.initials: G
authors.lastname: Saksena
authors.forename: Nicolas
authors.initials: N
authors.lastname: Stransky
authors.forename: Claudia
authors.initials: C
authors.lastname: Rangel-Escareño
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Fernandez-Lopez
authors.forename: Alfredo
authors.initials: A
authors.lastname: Hidalgo-Miranda
authors.forename: Jorge
authors.initials: J
authors.lastname: Melendez-Zajgla
authors.forename: Enrique
authors.initials: E
authors.lastname: Hernández-Lemus
authors.forename: Angela
authors.initials: A
authors.lastname: Schwarz-Cruz y Celis
authors.forename: Ivan
authors.initials: I
authors.lastname: Imaz-Rosshandler
authors.forename: Akinyemi I
authors.initials: AI
authors.lastname: Ojesina
authors.forename: Joonil
authors.initials: J
authors.lastname: Jung
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Pedamallu
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
mesh_terms: D020816:Amino Acid Motifs; D016000:Cluster Analysis; D004252:DNA Mutational Analysis; D059472:Exome; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic