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

Area of Science:

• Oncology
• Genetics
• Cancer Research

Background:

• Urothelial carcinoma (UC) is rarely linked to hereditary causes, but inherited factors are increasingly recognized.
• Current guidelines for genetic evaluation in UC are limited, focusing on early-onset disease or Lynch syndrome features.
• The full spectrum of germline variants and optimal genetic testing criteria for UC require further elucidation.

Purpose of the Study:

• To investigate the prevalence and spectrum of pathogenic germline variants in patients with urothelial carcinoma undergoing genetic evaluation.
• To identify clinicopathologic features associated with positive genetic testing outcomes in UC.
• To inform potential expansion of genetic evaluation criteria for urothelial carcinoma.

Main Methods:

• Retrospective analysis of 128 urothelial carcinoma patients referred for genetic evaluation (2002-2024).
• Recorded genetic testing outcomes, variant prevalence, and clinicopathologic features.
• Utilized Fisher's Exact test to compare factors between patients with and without pathogenic/likely pathogenic (P/LP) variants.

Main Results:

• 26.6% of patients had a confirmed P/LP variant, with Lynch syndrome and DNA damage repair genes being most common.
• A history of two or more additional cancers was significantly associated with a positive genetic test (P = .010).
• No significant association was found between genetic testing outcomes and age at diagnosis, tumor location, or initial disease stage.

Conclusions:

• A substantial proportion (26.6%) of selected urothelial carcinoma patients referred for genetic evaluation harbored pathogenic germline variants.
• History of multiple primary cancers is a potential indicator for genetic evaluation in UC.
• Findings suggest a potential role for broader genetic screening in urothelial carcinoma management.