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. BushellDaniel 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, Ryan D. Morin

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish
Article number4001
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Arthur, S. E., Jiang, A., Grande, B. M., Alcaide, M., Cojocaru, R., Rushton, C. K., Mottok, A., Hilton, L. K., Lat, P. K., Zhao, E. Y., Culibrk, L., Ennishi, D., Jessa, S., Chong, L., Thomas, N., Pararajalingam, P., Meissner, B., Boyle, M., Davidson, J., ... Morin, R. D. (2018). Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. Nature communications, 9(1), [4001]. https://doi.org/10.1038/s41467-018-06354-3