Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma

Sarah E. Arthur, Aixiang Jiang, Bruno M. Grande, Miguel Alcaide, Razvan Cojocaru, Christopher K. Rushton, Anja Mottok, Laura K. Hilton, Prince Kumar Lat, Eric Y. Zhao, Luka Culibrk, Daisuke Ennishi, Selin Jessa, Lauren Chong, Nicole Thomas, Prasath Pararajalingam, Barbara Meissner, Merrill Boyle, Jordan Davidson, Kevin R. Bushell, Daniel Lai, Pedro Farinha, Graham W. Slack, Gregg B. Morin, Sohrab Shah, Dipankar Sen, Steven J. M. Jones, Andrew J. Mungall, Randy D. Gascoyne, Timothy E. Audas, Peter Unrau, Marco A. Marra, Joseph M. Connors, Christian Steidl, David W. Scott and Ryan D. Morin ()
Additional contact information
Sarah E. Arthur: Simon Fraser University
Aixiang Jiang: Simon Fraser University
Bruno M. Grande: Simon Fraser University
Miguel Alcaide: Simon Fraser University
Razvan Cojocaru: Simon Fraser University
Christopher K. Rushton: Simon Fraser University
Anja Mottok: British Columbia Cancer Research Centre
Laura K. Hilton: Simon Fraser University
Prince Kumar Lat: Simon Fraser University
Eric Y. Zhao: British Columbia Cancer Research Centre
Luka Culibrk: British Columbia Cancer Research Centre
Daisuke Ennishi: British Columbia Cancer Research Centre
Selin Jessa: Simon Fraser University
Lauren Chong: British Columbia Cancer Research Centre
Nicole Thomas: Simon Fraser University
Prasath Pararajalingam: Simon Fraser University
Barbara Meissner: British Columbia Cancer Research Centre
Merrill Boyle: British Columbia Cancer Research Centre
Jordan Davidson: Simon Fraser University
Kevin R. Bushell: Simon Fraser University
Daniel Lai: British Columbia Cancer Research Centre
Pedro Farinha: British Columbia Cancer Research Centre
Graham W. Slack: British Columbia Cancer Research Centre
Gregg B. Morin: Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency
Sohrab Shah: British Columbia Cancer Research Centre
Dipankar Sen: Simon Fraser University
Steven J. M. Jones: Simon Fraser University
Andrew J. Mungall: Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency
Randy D. Gascoyne: British Columbia Cancer Research Centre
Timothy E. Audas: Simon Fraser University
Peter Unrau: Simon Fraser University
Marco A. Marra: Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency
Joseph M. Connors: British Columbia Cancer Research Centre
Christian Steidl: British Columbia Cancer Research Centre
David W. Scott: British Columbia Cancer Research Centre
Ryan D. Morin: Simon Fraser University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3′ UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.

Date: 2018
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DOI: 10.1038/s41467-018-06354-3

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