Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma
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Open Access
- 12 April 2018
- journal article
- research article
- Published by Massachusetts Medical Society in The New England Journal of Medicine
- Vol. 378 (15), 1396-1407
- https://doi.org/10.1056/nejmoa1801445
Abstract
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.)Keywords
Funding Information
- National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures (SPECS II) grant (5U01CA157581-05)
- Intramural Research Program of the NIH, National Cancer Institute
This publication has 30 references indexed in Scilit:
- Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS LymphomaCancer Cell, 2017
- Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphomaNature Medicine, 2015
- Loss of signalling via Gα13 in germinal centre B-cell-derived lymphomaNature, 2014
- Diacylglycerol Kinase ζ Limits B Cell Antigen Receptor–Dependent Activation of ERK Signaling to Inhibit Early Antibody ResponsesScience Signaling, 2013
- The Dok-3/Grb2 Protein Signal Module Attenuates Lyn Kinase-dependent Activation of Syk Kinase in B Cell Antigen Receptor MicroclustersOnline Journal of Public Health Informatics, 2013
- The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone developmentThe Journal of Experimental Medicine, 2012
- Pathogenesis of Human B Cell LymphomasAnnual Review of Immunology, 2012
- Down-regulation of B Cell Receptor Signaling by Hematopoietic Progenitor Kinase 1 (HPK1)-mediated Phosphorylation and Ubiquitination of Activated B Cell Linker Protein (BLNK)Journal of Biological Chemistry, 2012
- Oncogenically active MYD88 mutations in human lymphomaNature, 2010
- Protein kinase Cδ controls self-antigen-induced B-cell toleranceNature, 2002