title: Genetic heterogeneity of diffuse large B-cell lymphoma.
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-κB (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.
authors.affiliation: Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.forename: Vladimir
authors.initials: V
authors.lastname: Grubor
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Love
authors.forename: Anjishnu
authors.initials: A
authors.lastname: Banerjee
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Richards
authors.forename: Piotr A
authors.initials: PA
authors.lastname: Mieczkowski
authors.forename: Cherie
authors.initials: C
authors.lastname: Dunphy
authors.forename: William
authors.initials: W
authors.lastname: Choi
authors.forename: Wing Yan
authors.initials: WY
authors.lastname: Au
authors.forename: Gopesh
authors.initials: G
authors.lastname: Srivastava
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Lugar
authors.forename: David A
authors.initials: DA
authors.lastname: Rizzieri
authors.forename: Anand S
authors.initials: AS
authors.lastname: Lagoo
authors.forename: Leon
authors.initials: L
authors.lastname: Bernal-Mizrachi
authors.forename: Karen P
authors.initials: KP
authors.lastname: Mann
authors.forename: Christopher
authors.initials: C
authors.lastname: Flowers
authors.forename: Kikkeri
authors.initials: K
authors.lastname: Naresh
authors.forename: Andrew
authors.initials: A
authors.lastname: Evens
authors.forename: Leo I
authors.initials: LI
authors.lastname: Gordon
authors.forename: Magdalena
authors.initials: M
authors.lastname: Czader
authors.forename: Javed I
authors.initials: JI
authors.lastname: Gill
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Liu
authors.forename: Alice
authors.initials: A
authors.lastname: Fan
authors.forename: Katherine
authors.initials: K
authors.lastname: Walsh
authors.forename: Dereje
authors.initials: D
authors.lastname: Jima
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Smith
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Micah A
authors.initials: MA
authors.lastname: Luftig
authors.forename: Ting
authors.initials: T
authors.lastname: Ni
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Amy
authors.initials: A
authors.lastname: Chadburn
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: David
authors.initials: D
authors.lastname: Dunson
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Dave
mesh_terms: D000328:Adult; D001483:Base Sequence; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D059472:Exome; D015870:Gene Expression; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009154:Mutation; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C486018:PIK3CD protein, human