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Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing

Ryan D. Morin, Karen Mungall, Erin Pleasance, Andrew J. Mungall, Rodrigo Goya, Ryan D. Huff, David W. Scott, Jiarui Ding, Andrew Roth, Readman Chiu, Richard D. Corbett, Fong Chun Chan, Maria Mendez-Lago, Diane L. Trinh, Madison Bolger-Munro, Greg Taylor, Alireza Hadj Khodabakhshi, Susana Ben-Neriah, Julia Pon, Barbara Meissner, Bruce Woolcock, Noushin Farnoud, Sanja Rogic, Emilia L. Lim, Nathalie A. Johnson, Sohrab Shah, Steven Jones, Christian Steidl, Robert Holt, Inanc Birol, Richard Moore, Joseph M. Connors, Randy D. Gascoyne and Marco A. Marra

Key Points

  • Complete genome sequence analysis of 40 DLBCL tumors and 13 cell lines reveals novel somatic point mutations, rearrangements, and fusions.

  • Recurrence of mutations in genes involved in B-cell homing were identified in germinal center B-cell DLBCLs.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous cancer composed of at least 2 molecular subtypes that differ in gene expression and distribution of mutations. Recently, application of genome/exome sequencing and RNA-seq to DLBCL has revealed numerous genes that are recurrent targets of somatic point mutation in this disease. Here we provide a whole-genome-sequencing-based perspective of DLBCL mutational complexity by characterizing 40 de novo DLBCL cases and 13 DLBCL cell lines and combining these data with DNA copy number analysis and RNA-seq from an extended cohort of 96 cases. Our analysis identified widespread genomic rearrangements including evidence for chromothripsis as well as the presence of known and novel fusion transcripts. We uncovered new gene targets of recurrent somatic point mutations and genes that are targeted by focal somatic deletions in this disease. We highlight the recurrence of germinal center B-cell-restricted mutations affecting genes that encode the S1P receptor and 2 small GTPases (GNA13 and GNAI2) that together converge on regulation of B-cell homing. We further analyzed our data to approximate the relative temporal order in which some recurrent mutations were acquired and demonstrate that ongoing acquisition of mutations and intratumoral clonal heterogeneity are common features of DLBCL. This study further improves our understanding of the processes and pathways involved in lymphomagenesis, and some of the pathways mutated here may indicate new avenues for therapeutic intervention.

  • Submitted February 11, 2013.
  • Accepted May 10, 2013.
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