Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma |
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| Institution: | 1. Lank Center for Genitourinary Oncology Dana-Farber Cancer Institute Boston MA USA;2. Division of Pulmonary and Critical Care Medicine and Genetics, Department of Medicine, Brigham and Women’s Hospital Harvard Medical School Boston MA USA;3. Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School Boston MA USA;4. Division of Genetics Brigham and Women’s Hospital Boston MA USA;5. Cancer Program The Broad Institute of MIT and Harvard Cambridge MA USA;6. Department of Radiation Oncology, Brigham & Women’s Hospital/Dana-Farber Cancer Institute Harvard Medical School Boston MA USA;7. InVitae Corporation San Francisco CA USA;8. Division of Population Sciences, Center for Cancer Genetics and Prevention Dana-Farber Cancer Institute Boston MA USA;1. Lank Center for Genitourinary Oncology Dana-Farber Cancer Institute Boston MA USA;2. Division of Pulmonary and Critical Care Medicine and Genetics, Department of Medicine, Brigham and Women’s Hospital Harvard Medical School Boston MA USA;3. Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School Boston MA USA;4. Division of Genetics Brigham and Women’s Hospital Boston MA USA;5. Cancer Program The Broad Institute of MIT and Harvard Cambridge MA USA;6. Department of Radiation Oncology, Brigham & Women’s Hospital/Dana-Farber Cancer Institute Harvard Medical School Boston MA USA;7. InVitae Corporation San Francisco CA USA;8. Division of Population Sciences, Center for Cancer Genetics and Prevention Dana-Farber Cancer Institute Boston MA USA |
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| Abstract: | PurposeTo date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC).MethodsWe evaluated the frequency of germline pathogenic and likely pathogenic variants in 1038 patients with high-risk UC who underwent targeted clinical germline testing. Case–control enrichment analysis was performed to screen for pathogenic variant enrichment in 17 DNA repair genes in 1038 UC patients relative to cancer-free individuals.ResultsAmong 1038 patients with UC, the cumulative frequency of patients with pathogenic variants was 24%; 18.6% of patients harbored ≥1 actionable germline variant with preventive or therapeutic utility. MSH2 (34/969, 3.5%) and BRCA1/2 (38/867, 4.4%) germline variants had the highest frequency. Germline variants in DNA damage repair genes accounted for 78% of pathogenic germline variants. Compared to the cancer-free cohort, UC patients had significant variant enrichment in MSH2 (odds ratio OR]: 15.4, 95% confidence interval CI]: 7.1–32.7, p < 0.0001), MLH1 (OR: 15.9, 95% CI: 4.4–67.7, p < 0.0001), BRCA2 (OR: 5.7, 95% CI: 3.2–9.6, p < 0.0001), and ATM (OR: 3.8, 95% CI: 1.8–8.3, p = 0.02).ConclusionIn this study, 24% of UC patients harbored pathogenic germline variants and 18.6% had clinically actionable variants. MLH1 and MSH2 were validated as UC risk genes while ATM and BRCA2 were highlighted as potential UC predisposition genes. This work emphasizes the utility of germline testing in selected high-risk UC cohorts. |
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