Roland Schmitz1, George W Wright1, Da Wei Huang1, Calvin A Johnson1, James D Phelan1, James Q Wang1, Sandrine Roulland1, Monica Kasbekar1, Ryan M Young1, Arthur L Shaffer1, Daniel J Hodson1, Wenming Xiao1, Xin Yu1, Yandan Yang1, Hong Zhao1, Weihong Xu1, Xuelu Liu1, Bin Zhou1, Wei Du1, Wing C Chan1, Elaine S Jaffe1, Randy D Gascoyne1, Joseph M Connors1, Elias Campo1, Armando Lopez-Guillermo1, Andreas Rosenwald1, German Ott1, Jan Delabie1, Lisa M Rimsza1, Kevin Tay Kuang Wei1, Andrew D Zelenetz1, John P Leonard1, Nancy L Bartlett1, Bao Tran1, Jyoti Shetty1, Yongmei Zhao1, Dan R Soppet1, Stefania Pittaluga1, Wyndham H Wilson1, Louis M Staudt1. 1. 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.).
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).
Authors: Vu N Ngo; Ryan M Young; Roland Schmitz; Sameer Jhavar; Wenming Xiao; Kian-Huat Lim; Holger Kohlhammer; Weihong Xu; Yandan Yang; Hong Zhao; Arthur L Shaffer; Paul Romesser; George Wright; John Powell; Andreas Rosenwald; Hans Konrad Muller-Hermelink; German Ott; Randy D Gascoyne; Joseph M Connors; Lisa M Rimsza; Elias Campo; Elaine S Jaffe; Jan Delabie; Erlend B Smeland; Richard I Fisher; Rita M Braziel; Raymond R Tubbs; J R Cook; Denny D Weisenburger; Wing C Chan; Louis M Staudt Journal: Nature Date: 2010-12-22 Impact factor: 49.962
Authors: Matthew L Wheeler; Matthew B Dong; Robert Brink; Xiao-Ping Zhong; Anthony L DeFranco Journal: Sci Signal Date: 2013-10-15 Impact factor: 8.192
Authors: Michail S Lionakis; Kieron Dunleavy; Mark Roschewski; Brigitte C Widemann; John A Butman; Roland Schmitz; Yandan Yang; Diane E Cole; Christopher Melani; Christine S Higham; Jigar V Desai; Michele Ceribelli; Lu Chen; Craig J Thomas; Richard F Little; Juan Gea-Banacloche; Sucharita Bhaumik; Maryalice Stetler-Stevenson; Stefania Pittaluga; Elaine S Jaffe; John Heiss; Nicole Lucas; Seth M Steinberg; Louis M Staudt; Wyndham H Wilson Journal: Cancer Cell Date: 2017-05-25 Impact factor: 31.743
Authors: Wyndham H Wilson; Ryan M Young; Roland Schmitz; Yandan Yang; Stefania Pittaluga; George Wright; Chih-Jian Lih; P Mickey Williams; Arthur L Shaffer; John Gerecitano; Sven de Vos; Andre Goy; Vaishalee P Kenkre; Paul M Barr; Kristie A Blum; Andrei Shustov; Ranjana Advani; Nathan H Fowler; Julie M Vose; Rebecca L Elstrom; Thomas M Habermann; Jacqueline C Barrientos; Jesse McGreivy; Maria Fardis; Betty Y Chang; Fong Clow; Brian Munneke; Davina Moussa; Darrin M Beaupre; Louis M Staudt Journal: Nat Med Date: 2015-07-20 Impact factor: 53.440
Authors: Marion Lösing; Ingo Goldbeck; Birgit Manno; Thomas Oellerich; Tim Schnyder; Hanibal Bohnenberger; Björn Stork; Henning Urlaub; Facundo D Batista; Jürgen Wienands; Michael Engelke Journal: J Biol Chem Date: 2012-12-05 Impact factor: 5.157
Authors: Jagan R Muppidi; Roland Schmitz; Jesse A Green; Wenming Xiao; Adrien B Larsen; Sterling E Braun; Jinping An; Ying Xu; Andreas Rosenwald; German Ott; Randy D Gascoyne; Lisa M Rimsza; Elias Campo; Elaine S Jaffe; Jan Delabie; Erlend B Smeland; Rita M Braziel; Raymond R Tubbs; J R Cook; Dennis D Weisenburger; Wing C Chan; Nagarajan Vaidehi; Louis M Staudt; Jason G Cyster Journal: Nature Date: 2014-09-28 Impact factor: 49.962
Authors: Thomas Sommermann; Tomoharu Yasuda; Jonathan Ronen; Tristan Wirtz; Timm Weber; Ulrike Sack; Rebecca Caeser; Jingwei Zhang; Xun Li; Van Trung Chu; Anna Jauch; Kristian Unger; Daniel J Hodson; Altuna Akalin; Klaus Rajewsky Journal: Proc Natl Acad Sci U S A Date: 2020-06-10 Impact factor: 11.205
Authors: Kieron Dunleavy; Michelle A Fanale; Jeremy S Abramson; Ariela Noy; Paolo Fabrizio Caimi; Stefania Pittaluga; Samir Parekh; Ann Lacasce; John W Hayslip; Deepa Jagadeesh; Sunil Nagpal; Mary Jo Lechowicz; Rakesh Gaur; Andrea Lucas; Christopher Melani; Mark Roschewski; Seth M Steinberg; Elaine S Jaffe; Brad Kahl; Jonathan W Friedberg; Richard F Little; Nancy L Bartlett; Wyndham H Wilson Journal: Lancet Haematol Date: 2018-12 Impact factor: 18.959
Authors: Nancy L Bartlett; Wyndham H Wilson; Sin-Ho Jung; Eric D Hsi; Matthew J Maurer; Levi D Pederson; Mei-Yin C Polley; Brandelyn N Pitcher; Bruce D Cheson; Brad S Kahl; Jonathan W Friedberg; Louis M Staudt; Nina D Wagner-Johnston; Kristie A Blum; Jeremy S Abramson; Nishitha M Reddy; Jane N Winter; Julie E Chang; Ajay K Gopal; Amy Chadburn; Susan Mathew; Richard I Fisher; Kristy L Richards; Heiko Schöder; Andrew D Zelenetz; John P Leonard Journal: J Clin Oncol Date: 2019-04-02 Impact factor: 44.544
Authors: Suraya Elfrink; Charlotte M de Winde; Michiel van den Brand; Madeleine Berendsen; Margaretha G M Roemer; Frank Arnold; Luuk Janssen; Alie van der Schaaf; Erik Jansen; Patricia J T A Groenen; Astrid Eijkelenboom; Wendy Stevens; Corine J Hess; J Han van Krieken; Joost S P Vermaat; Arjen H G Cleven; Ruben A L de Groen; Viviana Neviani; Daphne de Jong; Sjoerd van Deventer; Blanca Scheijen; Annemiek B van Spriel Journal: Blood Date: 2019-07-31 Impact factor: 22.113
Authors: Michelle J Lee; Jean L Koff; Jeffrey M Switchenko; C Ileen Jhaney; R Andrew Harkins; Sharvil P Patel; Sandeep S Dave; Christopher R Flowers Journal: Cancer Date: 2020-05-29 Impact factor: 6.860
Authors: M K Gandhi; T Hoang; S C Law; S Brosda; K O'Rourke; J W D Tobin; F Vari; V Murigneux; L Fink; J Gunawardana; C Gould; H Oey; K Bednarska; S Delecluse; R U Trappe; L Merida de Long; M B Sabdia; G Bhagat; G Hapgood; E Blyth; L Clancy; J Wight; E Hawkes; L M Rimsza; A Maguire; K Bojarczuk; B Chapuy; C Keane Journal: Blood Date: 2021-03-18 Impact factor: 22.113