title: Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas.
abstract: Relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) is fatal in 90% of patients, and yet little is known about its biology.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada. Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.affiliation: Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada. McGill University, Montreal, Quebec, Canada.
authors.forename: Sarit
authors.initials: S
authors.lastname: Assouline
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Miguel
authors.initials: M
authors.lastname: Alcaide
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Arezoo
authors.initials: A
authors.lastname: Mohajeri
authors.affiliation: University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Johnston
authors.affiliation: University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Lauren
authors.initials: L
authors.lastname: Chong
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Jasleen
authors.initials: J
authors.lastname: Grewal
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fornika
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bushell
authors.affiliation: Department of Internal Medicine, Copenhagen University Hospital, Roskilde, Denmark.
authors.forename: Torsten Holm
authors.initials: TH
authors.lastname: Nielsen
authors.affiliation: Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Tina
authors.initials: T
authors.lastname: Petrogiannis-Haliotis
authors.affiliation: Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Crump
authors.affiliation: Sacre-Coeur Hospital, Montreal, Quebec, Canada.
authors.forename: Axel
authors.initials: A
authors.lastname: Tosikyan
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Grande
authors.affiliation: Department of Medicine, University of Dalhousie, Halifax, Nova Scotia, Canada.
authors.forename: David
authors.initials: D
authors.lastname: MacDonald
authors.affiliation: Quebec Clinical Research Organization in Cancer, Montreal, Quebec, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rousseau
authors.affiliation: McGill University, Montreal, Quebec, Canada.
authors.forename: Maryam
authors.initials: M
authors.lastname: Bayat
authors.affiliation: Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sesques
authors.affiliation: Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Remi
authors.initials: R
authors.lastname: Froment
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Albuquerque
authors.affiliation: Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Yury
authors.initials: Y
authors.lastname: Monczak
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Kathleen Klein
authors.initials: KK
authors.lastname: Oros
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada. Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: Celia
authors.initials: C
authors.lastname: Greenwood
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Riazalhosseini
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Arseneault
authors.affiliation: Department of Radiology, Jewish General Hospital, Montreal, McGill University, Quebec, Canada.
authors.forename: Errol
authors.initials: E
authors.lastname: Camlioglu
authors.affiliation: Department of Radiology, Jewish General Hospital, Montreal, McGill University, Quebec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Constantin
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarstrom
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China.
authors.forename: Roujun
authors.initials: R
authors.lastname: Peng
authors.affiliation: Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada. McGill University, Montreal, Quebec, Canada.
authors.forename: Koren K
authors.initials: KK
authors.lastname: Mann
authors.affiliation: Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada. McGill University, Montreal, Quebec, Canada. nathalie.johnson@mcgill.ca.
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000378:metabolism; D051925:CD79 Antigens / Q000235:genetics; D056743:Cyclin D3 / Q000235:genetics; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018858:Germinal Center / Q000378:metabolism; D006801:Humans; D053612:Janus Kinases / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D011446:Prospective Studies; D050800:STAT6 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D051925:CD79 Antigens; D056743:Cyclin D3; D000071161:Forkhead Box Protein O1; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009687:Nuclear Proteins; D050800:STAT6 Transcription Factor; D016159:Tumor Suppressor Protein p53; D051788:Myeloid-Lymphoid Leukemia Protein; D053612:Janus Kinases