Subject(s)
Lymphoma, B-Cell , Lymphoma, T-Cell , Animals , Dogs , Humans , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/pathology , Lymphoma, T-Cell/geneticsABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3' UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.
Subject(s)
Gene Expression Regulation, Neoplastic , Genes, Regulator/genetics , Genetic Variation , Genome, Human/genetics , Lymphoma, Large B-Cell, Diffuse/genetics , 3' Untranslated Regions/genetics , Adaptor Proteins, Signal Transducing , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Cell Line, Tumor , Exome/genetics , Genome-Wide Association Study , Germinal Center/metabolism , Germinal Center/pathology , Humans , I-kappa B Proteins/genetics , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Mutation , Nuclear Proteins/genetics , Receptors, IgG/genetics , Sequence Analysis, DNA , TranscriptomeABSTRACT
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 â¼9% 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.
