TY - JOUR
T1 - Genetic heterogeneity of diffuse large B-cell lymphoma
AU - Zhang, Jenny
AU - Grubor, Vladimir
AU - Love, Cassandra L.
AU - Banerjee, Anjishnu
AU - Richards, Kristy L.
AU - Mieczkowski, Piotr A.
AU - Dunphy, Cherie
AU - Choi, William
AU - Au, Wing Yan
AU - Srivastava, Gopesh
AU - Lugar, Patricia L.
AU - Rizzieri, David A.
AU - Lagoo, Anand S.
AU - Bernal-Mizrachi, Leon
AU - Mann, Karen P.
AU - Flowers, Christopher
AU - Naresh, Kikkeri
AU - Evens, Andrew
AU - Gordon, Leo I.
AU - Czader, Magdalena
AU - Gill, Javed I.
AU - Hsi, Eric D.
AU - Liu, Qingquan
AU - Fan, Alice
AU - Walsh, Katherine
AU - Jima, Dereje
AU - Smith, Lisa L.
AU - Johnson, Amy J.
AU - Byrd, John C.
AU - Luftig, Micah A.
AU - Ni, Ting
AU - Zhu, Jun
AU - Chadburn, Amy
AU - Levy, Shawn
AU - Dunson, David
AU - Dave, Sandeep S.
PY - 2013/1/22
Y1 - 2013/1/22
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.1205299110
DO - 10.1073/pnas.1205299110
M3 - Article
C2 - 23292937
AN - SCOPUS:84872856782
VL - 110
SP - 1398
EP - 1403
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 4
ER -