Introduction: Quite a few numbers of upper urinary tract urothelial carcinoma (UTUC) would be caused by germline pathogenic variants. Although mismatch repair (MMR) genes are known for pathogenicity for UTUC, the impact of other cancer-predisposing genes, such as BRCA1/2, on UTUC has never been thoroughly investigated despite the fact that panel sequencing is a standard method for advanced cancers. We conducted a case-control genetic analysis to clarify the association between these possible genes and UTUC in Japanese. Methods: We enrolled 210 patients with UTUC and 38,300 general subjects from Biobank Japan as controls. Twenty-seven genes were sequenced, including cancer-predisposing genes such as MMRs and BRCA1/2. Pathogenic variants were defined as follows; loss-of-function variants or variants registered as pathogenic in ClinVar. Results: After quality control, 209 patients with UTUC and 37,727 controls were analyzed. In the 27 analyzed genes, 4,769 germline variants, including 286 pathogenic variants, were confirmed. The pathogenic variants in MMR genes were detected in 1.44% of patients with UTUC and significantly associated with conceiving the UTUC (p = 1.30 × 10-3, OR 15.24). In the other genes, BRCA1 and BRCA2 had only one patient with pathogenic variants, and no significant association was verified. Conclusions: The significant association was observed between MMR genes and the prevalence of UTUC in Japanese. Other cancer-predisposing genes were not associated with UTUC in our study. It needs more patients to know whether these genes affect the risk of UTUC. SOURCE OF Funding: Japan Agency for Medical Research and Development (AMED) under Grant No. JP19kk0305010.
