Characterization of putative germline pathogenic variants in 27 candidate cancer-predisposing genes in 813 cats using...

In humans, about 5-10% of all cancers are caused by germline pathogenic variants (PVs) in cancer-predisposing genes, and their identification enables precision oncology approaches, such as surveillance for early detection, preventive medicine, and targeted therapy. Although cancer is a leading cause of death in cats, PVs have not been investigated for precision oncology. We developed a feline-specific multiplex targeted sequencing method to analyze 813 cats for putative PVs in 27 candidate feline cancer-predisposing genes. A total of 784 variants were identified, 13 of which were classified as putative PVs based on predicted truncating impact of amino acid sequence, clinical interpretation of corresponding variants in human, and in silico prediction on amino acid functions. Among 18 cats with one of the 13 putative PVs, seven (38.9%) had various types of confirmed or suspected tumor. Although PV carriers do not always develop cancer even in humans, putative PV carriers without tumors tended to be younger (1.83-16.58, years old, 9.16 years old on average) than the median age of tumor-bearing putative PV carriers (11.83 years old), suggesting that the proportion of affected cats may increase over time. Moreover, five cats with putative PVs in homologous recombination repair genes (BRCA2, RAD51C, or ATM) and two cats with those in mismatch repair genes (MSH2 and MSH6) may be candidates for targeted therapy with PARP inhibitors and immunotherapy with immune checkpoint inhibitors, respectively. These findings provide the first characterization of putative PVs in feline candidate cancer-predisposing genes, representing an important step toward genomics-informed oncology and risk stratification in cats.