To date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC).
We 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.
Among 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).
In 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.
Genetics in medicine : official journal of the American College of Medical Genetics. 2019 Dec 17 [Epub ahead of print]
Amin H Nassar, Sarah Abou Alaiwi, Saud H AlDubayan, Nicholas Moore, Kent W Mouw, David J Kwiatkowski, Toni K Choueiri, Catherine Curran, Jacob E Berchuck, Lauren C Harshman, Pier V Nuzzo, Nieves Martinez Chanza, Eliezer Van Allen, Edward D Esplin, Shan Yang, Thomas Callis, Judy E Garber, Huma Q Rana, Guru Sonpavde
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Department of Radiation Oncology, Brigham & Women's Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., InVitae Corporation, San Francisco, CA, USA., Division of Population Sciences, Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA., Division of Population Sciences, Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA. HumaQ_Rana@DFCI.HARVARD.EDU., Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. GuruP_Sonpavde@dfci.harvard.edu.