Molecular Epidemiological Study of Germline APC Variant Associated with Hereditary Gastrointestinal Polyposis in Dogs: Current Prevalence in Jack Russell Terriers in Japan and Breed Distribution

Background: Cases of gastrointestinal (GI) neoplastic polyps in Jack Russell Terriers (JRTs) have increased in Japan since the late 2000s. We recently demonstrated that JRTs with GI polyps heterozygously harbor an identical germline variant in the adenomatous polyposis coli ( APC ) gene, c.[462_463delinsTT]; therefore, this is an autosomal dominant hereditary disease. We conducted a molecular epidemiological study to explore the current prevalence of germline APC variants in JRTs in Japan and the breed distribution of this disease. Results: : Peripheral blood samples from 792 JRTs were collected at 93 veterinary hospitals in Japan in 2020. Using an established polymerase chain reaction-restriction fragment length polymorphism assay, the germline APC variant was detected in 15 JRTs, with an overall prevalence of 1.89%. The prevalence was not significantly different for sex, age, and coat type criteria. Notably, the variant carriers had a current or previous history of GI neoplastic polyps, providing further evidence of the association of the germline APC variant with GI polyposis. Pedigree analysis of carrier dogs revealed that the germline APC variant was no longer confined to a few specific bloodlines but was widely spread among JRTs in Japan. Furthermore, some ancestors of the carriers were from Australia or New Zealand, suggesting the possible presence of carriers in countries other than Japan. Next, we retrospectively investigated the germline APC variant status of dogs with GI epithelial tumors using genomic DNA samples extracted from archived pathological specimens, as well as those stored in a canine genome bank. In total, 67 purebred dogs of 24 breeds, including four JRTs, and four mixed-breed dogs were examined. While three variant carriers were found in JRTs, the germline APC variant was not detected in any of the other breeds. Conclusion: The current prevalence of the germline APC variant was approximately 2% in JRTs in Japan and the prevalence remained roughly flat during the last 15 years. In addition, hereditary GI polyposis associated with the variant was virtually specific to JRTs.