Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas

  • Ryan D. Morin
    1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • Sarit Assouline
    3Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
  • Miguel Alcaide
    1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • Arezoo Mohajeri
    1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • Rebecca L. Johnston
    5University of British Columbia, Vancouver, British Columbia, Canada.
  • Lauren Chong
    5University of British Columbia, Vancouver, British Columbia, Canada.
  • Jasleen Grewal
    1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • Stephen Yu
    1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • Daniel Fornika
    1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • Kevin Bushell
    1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • Torsten Holm Nielsen
    6Department of Internal Medicine, Copenhagen University Hospital, Roskilde, Denmark.
  • Tina Petrogiannis-Haliotis
    7Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.
  • Michael Crump
    8 Princess Margaret Hospital, Toronto, Ontario, Canada.
  • Axel Tosikyan
    9Sacre-Coeur Hospital, Montreal, Quebec, Canada.
  • Bruno M. Grande
    1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • David MacDonald
    10Department of Medicine, University of Dalhousie, Halifax, Nova Scotia, Canada.
  • Caroline Rousseau
    11Quebec Clinical Research Organization in Cancer, Montreal, Quebec, Canada.
  • Maryam Bayat
    4McGill University, Montreal, Quebec, Canada.
  • Pierre Sesques
    3Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
  • Remi Froment
    3Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
  • Marco Albuquerque
    1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • Yury Monczak
    7Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.
  • Kathleen Klein Oros
    12Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
  • Celia Greenwood
    12Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
  • Yasser Riazalhosseini
    15Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • Madeleine Arseneault
    15Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • Errol Camlioglu
    16Department of Radiology, Jewish General Hospital, Montreal, McGill University, Quebec, Canada.
  • André Constantin
    16Department of Radiology, Jewish General Hospital, Montreal, McGill University, Quebec, Canada.
  • Qiang Pan-Hammarstrom
    17Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden.
  • Roujun Peng
    17Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden.
  • Koren K. Mann
    3Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
  • Nathalie A. Johnson
    3Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.

抄録

<jats:title>Abstract</jats:title> <jats:p>Purpose: Relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) is fatal in 90% of patients, and yet little is known about its biology.</jats:p> <jats:p>Experimental Design: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions.</jats:p> <jats:p>Results: On the basis of a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3 (KMT2C), CCND3, NFKBIZ, and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-κB: NFKBIE and NFKBIZ. We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B-cell–type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes.</jats:p> <jats:p>Conclusions: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL. Clin Cancer Res; 22(9); 2290–300. ©2015 AACR.</jats:p>

収録刊行物

  • Clinical Cancer Research

    Clinical Cancer Research 22 (9), 2290-2300, 2016-05-01

    American Association for Cancer Research (AACR)

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