Pathogenic Germline Variant Prevalence and Genetic Testing Outcomes in Patients With Urothelial Carcinoma

Urothelial carcinoma (UC) is rarely attributed to hereditary causes, but recent studies suggest inherited factors may play a larger role. Current guidelines recommend genetic evaluation in patients with UC diagnosed at < 50 years old or features associated with Lynch syndrome. However, the full pathogenic germline variant landscape and optimal genetic evaluation criteria in UC remain poorly understood.

A retrospective analysis of all patients with UC referred for genetic evaluation between 2002 and 2024 was performed. Genetic testing outcomes, variant prevalence and characterization, and associated clinicopathologic features were recorded. Fisher's Exact test was used to compare factors between patients with pathogenic or likely pathogenic (P/LP) variant versus those with negative testing.

Overall, 128 patients underwent genetic evaluation. Median age at diagnosis was 59 (IQR: 48-68). Most (58.6%) had non-muscle invasive disease at initial diagnosis; 8.6% had metastatic disease. Pure urothelial histology was most frequent (71%). Upper tract disease was present at 14.8%. Among the cohort, 34 (26.6%) had a confirmed P/LP variant. The most common P/LP variants were Lynch syndrome-associated genes (9.4%) and DNA damage repair genes (9.4%). Having a history of ≥ 2 additional cancers was associated with a positive genetic test (P = .010). Otherwise, there were no statistically significant differences in testing outcomes based on age at diagnosis, primary tumor location, or initial stage at diagnosis.

Among patients with UC referred for genetic evaluation, 26.6% had a confirmed P/LP variant, although this cohort was a selected population. Age and traditional clinicopathologic features were not associated with testing results, though history of ≥ 2 additional cancers was associated. These findings may suggest a broader use of genetic evaluation in UC.