title: Genetic inactivation of TRAF3 in canine and human B-cell lymphoma.
abstract: Non-Hodgkin lymphomas (NHLs) are the most common cancer to affect pet dogs. In contrast to the many genes whose mutation contributes to lymphomagenesis in humans, relatively little is known about the acquired genetic alterations that lead to canine B-cell lymphomas (cBCLs). We performed a survey of 84 canine NHL tumors to identify genes affected by somatic point mutations. We found mutations affecting TRAF3, which encodes a negative regulator of nuclear factor (NF)-κB, to be a common feature of cBCLs, with mutations observed in 44% of tumors including a combination of somatic and rare germ-line variants. Overall, 30% of the tumors contained ≥1 somatic TRAF3 mutation. The majority of mutations are predicted to cause loss of TRAF3 protein including those impacting reading frame and splicing. To determine whether TRAF3 loss might be relevant to human NHL, we also analyzed 148 human diffuse large B-cell lymphoma (DLBCL) tumors and identified loss of TRAF3 as a common event, affecting ∼9% of DLBCLs, and reduced expression of TRAF3 among deleted cases. This study implicates mutations affecting NF-κB activity as a novel genetic commonality between human and canine NHLs and supports the potential utility of cBCLs with mutated TRAF3 as a model of the more aggressive activated B-cell subgroup of DLBCL.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Bushell
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Yukyoung
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada; Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada; and.
authors.forename: Fong Chun
authors.initials: FC
authors.lastname: Chan
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors.forename: Susana
authors.initials: S
authors.lastname: Ben-Neriah
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Andrew
authors.initials: A
authors.lastname: Jenks
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Miguel
authors.initials: M
authors.lastname: Alcaide
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-6178-3585
authors.initials: D
authors.lastname: Fornika
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Bruno M
authors.identifier: http://orcid.org/0000-0002-4621-1589
authors.initials: BM
authors.lastname: Grande
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Sarah
authors.initials: S
authors.lastname: Arthur
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada;
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada; Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Ryan D
authors.identifier: http://orcid.org/0000-0003-2932-7800
authors.initials: RD
authors.lastname: Morin
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D004285:Dogs; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D048008:TNF Receptor-Associated Factor 3