Genetic heterogeneity of diffuse large B-cell lymphoma

Jenny Zhang, Vladimir Grubor, Cassandra L. Love, Anjishnu Banerjee, Kristy L. Richards, Piotr A. Mieczkowski, Cherie Dunphy, William Choi, Wing Yan Au, Gopesh Srivastava, Patricia L. Lugar, David A. Rizzieri, Anand S. Lagoo, Leon Bernal-Mizrachi, Karen P. Mann, Christopher Flowers, Kikkeri Naresh, Andrew Evens, Leo I. Gordon, Magdalena CzaderJaved I. Gill, Eric D. Hsi, Qingquan Liu, Alice Fan, Katherine Walsh, Dereje Jima, Lisa L. Smith, Amy J. Johnson, John C. Byrd, Micah A. Luftig, Ting Ni, Jun Zhu, Amy Chadburn, Shawn Levy, David Dunson, Sandeep S. Dave

Research output: Contribution to journalArticlepeer-review

334 Scopus citations

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-?B (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.

Original languageEnglish (US)
Pages (from-to)1398-1403
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number4
DOIs
StatePublished - Jan 22 2013

ASJC Scopus subject areas

  • General

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