Mutational Screening Of Brca1/2 Genes In 667 Spontaneous Canine Tumors.

Abstract BRCA1 and BRCA2 (Breast cancer susceptibility gene 1 and 2) are tumor suppressor genes that maintain genomic stability by repairing damaged DNA. The proteins coded by these genes are involved in complexes that activate the repair of double strand breaks (DSBs) and initiate homologous recombination (HR). BRCA mutations are common in various forms of human cancers, most notably breast cancer, and previously described in canine tumors. Tumors in canines and humans share many characteristics, including: inter-individual and intra-tumoral heterogeneity, biological behavior, similar tumor microenvironments, and similar genomic mutations. This study interrogates naturally-occuring cancers in dogs as a tool that can add valuable information to our understanding of similar tumors in people. A total of 667 tumors of various histologies were obtained from client-owned dogs and sequenced on the FidoCure® Next-generation sequencing (NGS) panel as part of their veterinary precision medicine platform. Mutations in BRCA1 and BRCA2 were among the 5 most common genetic mutations identified. BRCA1 or BRCA2 mutations were identified in 71.8% (479/667) of tumors overall; 36.4% (n=243) BRCA1 mutations, 33.7% (n=225) BRCA2 mutations, and 1.6% (n=11) BRCA1/2 co-mutations. Germline single-nucleotide polymorphisms (SNPs) represented 56% (136/243) and 61% (138/225) of BRCA1 and BRCA2 mutations, respectively. Removing SNPs and focusing on single-nucleotide variants (SNVs), 16.1% of cases (107/667) had BRCA1 mutations, 13.0% (87/667) had BRCA2 mutations, and 1.65% (11/667) had both BRCA1 and BRCA2 mutations. Utilizing Protein Variation Effect Analyzed (PROVEAN) and Sort Intolerant From Tolerant (SIFT) bioinformatic tools to assess the functional significance of BRCA1 and BRCA2 missense variants, 69.2% and 54.8% of mutations, respectively, were predicted as pathogenic/deleterious. Interestingly, a search of the 2017 MSK IMPACT dataset reveals a pan-cancer prevalence in humans of 2.0% BRCA1 variants (216/10,945 cases) and 3.6% BRCA2 variants (399/10,945 cases). Looking at cancer histologies in dogs, BRCA1 variants were identified in 14.1% of soft tissue sarcomas (STS), 11.4% of apocrine gland anal-sac adenocarcinomas (AGASACA), 11.1% of mast cell tumors (MCT), 10.9% of osteosarcomas (OSA), and 10% of thyroid carcinomas. BRCA2 mutations were identified in 33.3% of MCTs, 32.1% of STSs, 23.8% of histiocytic sarcomas, 17.2% of OSAs, and 16.3% of AGASACAs. This analysis of BRCA1/2 mutations in dogs highlights the value of companion animals as a model for human disease to better understand the contribution of these genes in tumorigenesis and for exploring different targeted therapeutic interventions. Further evaluation of the efficacy of PARP inhibitors, either with or without chemotherapy and/or radiotherapy, in tumors with BRCA1/2 mutations in dogs may reveal information that can then be used to benefit humans with similar malignancies. Citation Format: Benjamin Lewis, Gerry Post, Garrett Harvey, Lindsay Lambert, Aubrey Miller, Rilke Van Buren, Christina Lopes, Lucas Rodrigues. Mutational screening of BRCA1/2 genes in 667 spontaneous canine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2991.