Genetic alterations span bladder and upper tract urothelial cancer

In this video, Steven Monda, MD, a clinical instructor at the University of Michigan in Ann Arbor, discusses the study “Germline Variants in Urothelial Cancer: Prevalence, Clinical Context, and Implications for Genetic Testing,” which evaluated the frequency and clinical significance of pathogenic germline variants among patients with urothelial cancer referred for genetic testing.

Using a large national cohort of 3561 patients tested through Myriad Genetics—primarily individuals with bladder cancer, upper tract urothelial cancer (UTUC), or both—the investigators assessed the prevalence of pathogenic or likely pathogenic variants, with a focus on mismatch repair (MMR) genes associated with Lynch syndrome (MSH2, MSH6, MLH1, PMS2) and homologous recombination repair (HRR) genes such as BRCA1 and BRCA2. Findings were validated in a smaller cohort of 35 patients with Lynch syndrome and urothelial cancer from the University of Michigan.

Overall, germline pathogenic variants were common, identified in approximately 1 in 7 tested patients. Lynch syndrome–associated variants, particularly MSH2, were highly enriched among patients with UTUC, with about 35% testing positive for an MMR gene variant. However, because bladder cancer is far more prevalent, most MSH2 carriers in absolute numbers presented with bladder-only disease, underscoring that Lynch-associated urothelial cancer is not limited to the upper tract. This phenotypic variability suggests that site-restricted testing strategies would miss a substantial proportion of carriers.

The study also highlighted the importance of prior and family cancer history. Prior malignancies were frequent and closely aligned with the underlying germline variant: colorectal and endometrial cancers commonly preceded urothelial cancer in Lynch syndrome, while breast and prostate cancers were typical among HRR mutation carriers. Family history proved particularly informative, as most MSH2 carriers had relatives with colorectal cancer, despite relatively few reporting a family history of urothelial cancer.

Collectively, these findings support a broader, history-driven approach to germline testing in urothelial cancer. Reliance on age thresholds, tumor site alone, or reflex immunohistochemistry risks under-identifying patients with actionable germline variants, emphasizing the need for comprehensive personal and family history assessment to guide genetic evaluation.

REFERENCE

1. Monda S, Oh E, Ghani K, et al. Germline variants in urothelial cancer: Prevalence, clinical context, and implications for genetic testing. Presented at: Society of Urologic Oncology Annual Meeting; December 2-5, 2025; Phoenix, Arizona. Abstract 169. https://suo-abstracts.secure-platform.com/a/gallery/rounds/24/details/4739