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Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.

Roland Schmitz1, George W Wright1, Da Wei Huang1

  • 1From 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.).

The New England Journal of Medicine
|April 12, 2018
PubMed
Summary

Researchers identified four genetic subtypes of diffuse large B-cell lymphoma (DLBCL): MCD, BN2, N1, and EZB. These subtypes show distinct genetic profiles, clinical outcomes, and potential therapeutic vulnerabilities, paving the way for precision medicine in DLBCL.

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Area of Science:

  • Hematology
  • Oncology
  • Genetics

Background:

  • Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous cancer with subgroups (ABC, GCB) identified by gene expression.
  • These subgroups correlate with differential responses to chemotherapy and targeted agents.
  • Understanding DLBCL's genetic landscape is crucial for developing new therapeutic strategies.

Purpose of the Study:

  • To identify distinct genetic subtypes of DLBCL based on shared genomic abnormalities.
  • To uncover potential therapeutic vulnerabilities associated with specific genetic alterations in DLBCL.
  • To correlate genetic subtypes with phenotypic characteristics and clinical outcomes.

Main Methods:

  • Analysis of 574 DLBCL biopsy samples using whole-exome sequencing, transcriptome sequencing, and array-based DNA copy-number analysis.
  • Targeted sequencing of 372 genes to identify recurrent genetic aberrations.
  • Development of an algorithm to discover genetic subtypes based on co-occurring genetic alterations.

Main Results:

  • Four prominent genetic subtypes of DLBCL were identified: MCD, BN2, N1, and EZB.
  • Each subtype was characterized by specific recurrent genetic aberrations (e.g., MYD88 mutations in MCD, BCL6 fusions in BN2).
  • Subtypes exhibited distinct gene-expression signatures, responses to immunochemotherapy, and survival outcomes (favorable for BN2/EZB, inferior for MCD/N1).

Conclusions:

  • The identified genetic subtypes of DLBCL possess distinct genotypic, epigenetic, and clinical features.
  • These findings offer a potential new classification system (nosology) for DLBCL.
  • The study highlights the potential for precision-medicine strategies tailored to the genetic subtypes of DLBCL.