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N Engl J Med. 2018 Apr 12;378(15):1396-1407. doi: 10.1056/NEJMoa1801445.

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.

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From the Lymphoid Malignancies Branch (R.S., D.W.H., J.D.P., J.Q.W., S.R., M.K., R.M.Y., A.L.S., D.J.H., W. Xiao, X.Y., Y.Y., H.Z., W. Xu, W.H.W., L.M.S.), the Biometric Research Program, Division of Cancer Diagnosis and Treatment (G.W.W.), and the Laboratory of Pathology, Center for Cancer Research (E.S.J., S.P.), National Cancer Institute, and the Office of Intramural Research, Center for Information Technology (C.A.J., X.L., B.Z., W.D.), National Institutes of Health, Bethesda, and the Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick (B.T., J.S., Y.Z., D.R.S.) - all in Maryland; the Department of Pathology, City of Hope National Medical Center, Duarte, CA (W.C.C.); the BC Cancer Agency, Vancouver, BC (R.D.G., J.M.C.), and the University Health Network, Laboratory Medicine Program, Toronto General Hospital and University of Toronto, Toronto (J.D.) - both in Canada; the Hospital Clinic of Barcelona, University of Barcelona, Institute for Biomedical Research August Pi I Sunyer, Barcelona (E.C., A.L.-G.); the Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg (A.R.), and the Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart (G.O.) - all in Germany; the Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ (L.M.R.); the National Cancer Centre of Singapore, Singapore (K.T.K.W.); Memorial Sloan Kettering Cancer Center (A.D.Z.) and Weill Cornell Medicine (J.P.L.) - both in New York; the Department of Medicine, Washington University School of Medicine, St. Louis (N.L.B.); and the Alliance for Clinical Trials in Oncology, Chicago (A.D.Z., J.P.L., N.L.B.).



Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics.


We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations.


We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition.


We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).

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