Genetics and pathogenesis of diffuse large B-Cell lymphoma

R. Schmitz, G. W. Wright, D. W. Huang, C. A. Johnson, J. D. Phelan, J. Q. Wang, S. Roulland, M. Kasbekar, R. M. Young, A. L. Shaffer, D. J. Hodson, W. Xiao, X. Yu, Y. Yang, H. Zhao, W. Xu, X. Liu, B. Zhou, W. Du, W. C. ChanE. S. Jaffe, R. D. Gascoyne, J. M. Connors, E. Campo, A. Lopez-Guillermo, A. Rosenwald, G. Ott, J. Delabie, Lisa M Rimsza, K. Tay Kuang Wei, A. D. Zelenetz, J. P. Leonard, N. L. Bartlett, B. Tran, J. Shetty, Y. Zhao, D. R. Soppet, S. Pittaluga, W. H. Wilson, L. M. Staudt

Research output: Contribution to journalArticle

172 Citations (Scopus)

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.)

Original languageEnglish (US)
Pages (from-to)1396-1407
Number of pages12
JournalNew England Journal of Medicine
Volume378
Issue number15
DOIs
StatePublished - Apr 12 2018
Externally publishedYes

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Lymphoma, Large B-Cell, Diffuse
Mutation
B-Lymphocytes
B-Cell Lymphoma
Transcriptome
Genes
Exome
Precision Medicine
Germinal Center
National Institutes of Health (U.S.)
Gene Expression Profiling
Oligonucleotide Array Sequence Analysis
Epigenomics
Biopsy
Drug Therapy
Therapeutics
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Schmitz, R., Wright, G. W., Huang, D. W., Johnson, C. A., Phelan, J. D., Wang, J. Q., ... Staudt, L. M. (2018). Genetics and pathogenesis of diffuse large B-Cell lymphoma. New England Journal of Medicine, 378(15), 1396-1407. https://doi.org/10.1056/NEJMoa1801445

Genetics and pathogenesis of diffuse large B-Cell lymphoma. / Schmitz, R.; Wright, G. W.; Huang, D. W.; Johnson, C. A.; Phelan, J. D.; Wang, J. Q.; Roulland, S.; Kasbekar, M.; Young, R. M.; Shaffer, A. L.; Hodson, D. J.; Xiao, W.; Yu, X.; Yang, Y.; Zhao, H.; Xu, W.; Liu, X.; Zhou, B.; Du, W.; Chan, W. C.; Jaffe, E. S.; Gascoyne, R. D.; Connors, J. M.; Campo, E.; Lopez-Guillermo, A.; Rosenwald, A.; Ott, G.; Delabie, J.; Rimsza, Lisa M; Tay Kuang Wei, K.; Zelenetz, A. D.; Leonard, J. P.; Bartlett, N. L.; Tran, B.; Shetty, J.; Zhao, Y.; Soppet, D. R.; Pittaluga, S.; Wilson, W. H.; Staudt, L. M.

In: New England Journal of Medicine, Vol. 378, No. 15, 12.04.2018, p. 1396-1407.

Research output: Contribution to journalArticle

Schmitz, R, Wright, GW, Huang, DW, Johnson, CA, Phelan, JD, Wang, JQ, Roulland, S, Kasbekar, M, Young, RM, Shaffer, AL, Hodson, DJ, Xiao, W, Yu, X, Yang, Y, Zhao, H, Xu, W, Liu, X, Zhou, B, Du, W, Chan, WC, Jaffe, ES, Gascoyne, RD, Connors, JM, Campo, E, Lopez-Guillermo, A, Rosenwald, A, Ott, G, Delabie, J, Rimsza, LM, Tay Kuang Wei, K, Zelenetz, AD, Leonard, JP, Bartlett, NL, Tran, B, Shetty, J, Zhao, Y, Soppet, DR, Pittaluga, S, Wilson, WH & Staudt, LM 2018, 'Genetics and pathogenesis of diffuse large B-Cell lymphoma', New England Journal of Medicine, vol. 378, no. 15, pp. 1396-1407. https://doi.org/10.1056/NEJMoa1801445
Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ et al. Genetics and pathogenesis of diffuse large B-Cell lymphoma. New England Journal of Medicine. 2018 Apr 12;378(15):1396-1407. https://doi.org/10.1056/NEJMoa1801445
Schmitz, R. ; Wright, G. W. ; Huang, D. W. ; Johnson, C. A. ; Phelan, J. D. ; Wang, J. Q. ; Roulland, S. ; Kasbekar, M. ; Young, R. M. ; Shaffer, A. L. ; Hodson, D. J. ; Xiao, W. ; Yu, X. ; Yang, Y. ; Zhao, H. ; Xu, W. ; Liu, X. ; Zhou, B. ; Du, W. ; Chan, W. C. ; Jaffe, E. S. ; Gascoyne, R. D. ; Connors, J. M. ; Campo, E. ; Lopez-Guillermo, A. ; Rosenwald, A. ; Ott, G. ; Delabie, J. ; Rimsza, Lisa M ; Tay Kuang Wei, K. ; Zelenetz, A. D. ; Leonard, J. P. ; Bartlett, N. L. ; Tran, B. ; Shetty, J. ; Zhao, Y. ; Soppet, D. R. ; Pittaluga, S. ; Wilson, W. H. ; Staudt, L. M. / Genetics and pathogenesis of diffuse large B-Cell lymphoma. In: New England Journal of Medicine. 2018 ; Vol. 378, No. 15. pp. 1396-1407.
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title = "Genetics and pathogenesis of diffuse large B-Cell lymphoma",
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.)",
author = "R. Schmitz and Wright, {G. W.} and Huang, {D. W.} and Johnson, {C. A.} and Phelan, {J. D.} and Wang, {J. Q.} and S. Roulland and M. Kasbekar and Young, {R. M.} and Shaffer, {A. L.} and Hodson, {D. J.} and W. Xiao and X. Yu and Y. Yang and H. Zhao and W. Xu and X. Liu and B. Zhou and W. Du and Chan, {W. C.} and Jaffe, {E. S.} and Gascoyne, {R. D.} and Connors, {J. M.} and E. Campo and A. Lopez-Guillermo and A. Rosenwald and G. Ott and J. Delabie and Rimsza, {Lisa M} and {Tay Kuang Wei}, K. and Zelenetz, {A. D.} and Leonard, {J. P.} and Bartlett, {N. L.} and B. Tran and J. Shetty and Y. Zhao and Soppet, {D. R.} and S. Pittaluga and Wilson, {W. H.} and Staudt, {L. M.}",
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TY - JOUR

T1 - Genetics and pathogenesis of diffuse large B-Cell lymphoma

AU - Schmitz, R.

AU - Wright, G. W.

AU - Huang, D. W.

AU - Johnson, C. A.

AU - Phelan, J. D.

AU - Wang, J. Q.

AU - Roulland, S.

AU - Kasbekar, M.

AU - Young, R. M.

AU - Shaffer, A. L.

AU - Hodson, D. J.

AU - Xiao, W.

AU - Yu, X.

AU - Yang, Y.

AU - Zhao, H.

AU - Xu, W.

AU - Liu, X.

AU - Zhou, B.

AU - Du, W.

AU - Chan, W. C.

AU - Jaffe, E. S.

AU - Gascoyne, R. D.

AU - Connors, J. M.

AU - Campo, E.

AU - Lopez-Guillermo, A.

AU - Rosenwald, A.

AU - Ott, G.

AU - Delabie, J.

AU - Rimsza, Lisa M

AU - Tay Kuang Wei, K.

AU - Zelenetz, A. D.

AU - Leonard, J. P.

AU - Bartlett, N. L.

AU - Tran, B.

AU - Shetty, J.

AU - Zhao, Y.

AU - Soppet, D. R.

AU - Pittaluga, S.

AU - Wilson, W. H.

AU - Staudt, L. M.

PY - 2018/4/12

Y1 - 2018/4/12

N2 - 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.)

AB - 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.)

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U2 - 10.1056/NEJMoa1801445

DO - 10.1056/NEJMoa1801445

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VL - 378

SP - 1396

EP - 1407

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

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