Incidence of Germline Genetic Variants in Patients with a Urinary Tract Cancer and Association with Outcomes.

Lynch syndrome (LS) and germline DNA damage repair (DDR) mutations have been described in urothelial carcinoma (UC). However, the incidence in unselected cohorts and the impact on outcomes remain unclear. We performed a retrospective study to determine the frequency of pathogenic/likely pathogenic (P/LP) germline variants in 78 known cancer predisposition genes among 273 patients with urinary tract cancer (UTC) of the bladder, renal pelvis, ureter, and/or urethra and validated the frequency in an independent cohort of 5972 patients. We identified variants in germline whole-exome sequencing that were overrepresented in UTC. We measured associations with treatment-related outcomes. In unselected cohorts, 9.3-9.5% of the patients with UTC harbored a variant in a cancer predisposition gene. No clinicodemographic variable predicted the presence of a P/LP variant. LS was found in 0.7-0.8% of the patients who were more likely to have upper tract disease and strong personal and family histories of malignancy. Non-Lynch DDR variants occurred in 6.6-8.0% of the patients, most often in CHEK2, BRCA1, BRCA2, and ATM. Very small cohorts of patients with UC and LS or a DDR variant responded well to immune checkpoint inhibitors (ICIs) or platinum chemotherapy, respectively. Standard variant calling methods may miss large deletions. The incidence of P/LP germline variants in UTC is clinically meaningful, and more than one-third of the patients are missed with current guidelines. The response of UC with LS to ICI and with DDR to platinum is hypothesis generating and warrants further investigation.