Approximately 10% to 14% of urothelial cancer patients harbor pathogenic germline variants, rising to 15% to 20% in upper tract urothelial carcinoma (UTUC), where mismatch repair (MMR) gene variants associated with Lynch syndrome are a major contributor. Despite this substantial burden of germline mutation risk, urothelial cancer still lacks the guideline framework that has made germline testing standard practice in comparable malignancies. Lynch syndrome is the most common hereditary cause of urothelial cancer, and MSH2 confers the greatest urothelial cancer risk among the 4 MMR genes. MMR-deficient tumors show marked sensitivity to immune checkpoint inhibition across tumor types. Beyond Lynch syndrome, germline variants in homologous recombination repair (HRR) genes, particularly BRCA2, may be enriched in urothelial cancer and have important cascade testing implications for families, regardless of therapeutic actionability. Tumor-based MMR screening using immunohistochemistry and microsatellite instability testing provides a practical but imperfect route to detection, with tissue availability posing a particular challenge in UTUC. In this review, we outline current guidelines, summarize the prevalence of germline pathogenic (and likely pathogenic) variants across the urothelial cancer spectrum, discuss pathways for MMR testing, and identify key gaps in the field-including the case for universal germline evaluation in UTUC, the absence of a bladder cancer testing framework, and the opportunity represented by somatic-to-germline testing pathways.
Urologic oncology. 2026 Jul 28 [Epub ahead of print]
Steven M Monda, Tobias Else, Alex Zhu, Samuel D Kaffenberger, Robert M Humble, Zachery R Reichert, Todd M Morgan, Thenappan Chandrasekar, Mev Dominguez-Valentin, Elena M Stoffel, Udit Singhal
Department of Urology, University of Michigan, Ann Arbor, MI. Electronic address: ., Division of Genetic Medicine, University of Michigan, Ann Arbor, MI; Division of Metabolism, Endocrinology, & Diabetes, University of Michigan, Ann Arbor, MI., Department of Urology, University of Washington, Seattle, WA., Department of Urology, University of Michigan, Ann Arbor, MI., Department of Pathology, University of Michigan, Ann Arbor, MI., Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI., Department of Urology, University of California Davis, Sacramento, CA., Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway., Division of Genetic Medicine, University of Michigan, Ann Arbor, MI; Division of Gastroenterology, University of Michigan, Ann Arbor, MI.