Consensus-based somatic variant-calling method correlates FBXW7 mutations with poor prognosis in canine B-cell lymphoma

Abstract

INTRODUCTIONCanine Lymphoma (CL) is the most commonly diagnosed malignancy in the domestic dog, with estimates reaching 80,000 new cases per year in the United States. Understanding of genetic factors involved in development and progression of canine B-Cell Lymphoma (cBCL), the most common of the two major subtypes of CL, can help guide efforts to prevent, diagnose, and treat disease in dogs. Such findings also have implications for human Non-Hodgkin Lymphoma (NHL), as pet dogs have recently emerged as an important translational model due to the many shared histopathological, biological, and clinical characteristics between cBCL and NHL. OBJECTIVESWe aimed to identify potential driver mutations in cBCL and detect associations between affected genes and differential clinical outcomes. METHODSUsing exome sequencing of paired normal and tumor tissues from 71 dogs of various breeds with cBCL, we identified somatic variants with a consensus approach: keeping variants called by both MuTect2 and with high-confidence by VarScan 2. We predicted effects of these variants using SnpEff then measured associations between mutated genes and survival times from clinical data available for 62 cohort dogs using a multivariate Cox Proportional Hazards Model. RESULTSMutations in FBXW7, a gene commonly mutated in both human and canine cancers including lymphoma, were associated with shorter overall survival (OS; p=0.01, HR 3.3 [1.4-7.6]). The two most frequently mutated codons of FBXW7 in our cohort correspond to the most frequently mutated codons in human cancers. CONCLUSIONSOur findings show that exome sequencing results can be combined with clinical data to identify key mutations associated with prognosis in cBCL. These results may have implications for precision medicine in dogs and also allow subsets of dogs to serve as models for specific subtypes of human lymphoma. Translational RelevanceIdentifying tumor biomarkers associated with clinical outcomes has been a major driver in improved success in treating many types of human cancers, including Non-Hodgkin lymphoma (NHL). Since canine B-cell Lymphoma (cBCL) shares many clinically identifiable characteristics with NHL, our detection of recurring mutations in certain genes in cBCL and their association with clinical outcomes stands to benefit both humans and dogs. If common canine lymphoma subtypes show mutational similarity to certain human subtypes, then therapies found to be effective for a subtype in one species may be more likely to improve treatment response in the analogous subtype in the other.