Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas
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- Ryan D. Morin
- 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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- Sarit Assouline
- 3Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
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- Miguel Alcaide
- 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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- Arezoo Mohajeri
- 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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- Rebecca L. Johnston
- 5University of British Columbia, Vancouver, British Columbia, Canada.
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- Lauren Chong
- 5University of British Columbia, Vancouver, British Columbia, Canada.
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- Jasleen Grewal
- 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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- Stephen Yu
- 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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- Daniel Fornika
- 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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- Kevin Bushell
- 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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- Torsten Holm Nielsen
- 6Department of Internal Medicine, Copenhagen University Hospital, Roskilde, Denmark.
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- Tina Petrogiannis-Haliotis
- 7Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.
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- Michael Crump
- 8 Princess Margaret Hospital, Toronto, Ontario, Canada.
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- Axel Tosikyan
- 9Sacre-Coeur Hospital, Montreal, Quebec, Canada.
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- Bruno M. Grande
- 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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- David MacDonald
- 10Department of Medicine, University of Dalhousie, Halifax, Nova Scotia, Canada.
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- Caroline Rousseau
- 11Quebec Clinical Research Organization in Cancer, Montreal, Quebec, Canada.
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- Maryam Bayat
- 4McGill University, Montreal, Quebec, Canada.
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- Pierre Sesques
- 3Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
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- Remi Froment
- 3Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
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- Marco Albuquerque
- 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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- Yury Monczak
- 7Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.
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- Kathleen Klein Oros
- 12Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
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- Celia Greenwood
- 12Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
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- Yasser Riazalhosseini
- 15Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
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- Madeleine Arseneault
- 15Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
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- Errol Camlioglu
- 16Department of Radiology, Jewish General Hospital, Montreal, McGill University, Quebec, Canada.
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- André Constantin
- 16Department of Radiology, Jewish General Hospital, Montreal, McGill University, Quebec, Canada.
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- Qiang Pan-Hammarstrom
- 17Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden.
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- Roujun Peng
- 17Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden.
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- Koren K. Mann
- 3Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
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- Nathalie A. Johnson
- 3Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
Description
<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>
Journal
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- Clinical Cancer Research
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Clinical Cancer Research 22 (9), 2290-2300, 2016-05-01
American Association for Cancer Research (AACR)
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Details 詳細情報について
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- CRID
- 1360855568826443136
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- ISSN
- 15573265
- 10780432
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- Data Source
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- Crossref