Common deleterious germline variants shape the urothelial cancer genome

Introduction The prevalence and biological consequences of deleterious germline variants (DGVs) in urothelial cancer (UC) are unknown. Methods We performed whole-exome sequencing (WES) of 158 tumors and corresponding germline DNA from 80 UC patients at Weill-Cornell Medicine (WCM). We developed a novel computational framework (DGVar) to detect DGVs from germline WES data and predict their biological functions. We used strict criteria to identify truncating variants in 1604 tumor suppressor genes (TSGs) from germline WES data. We assessed germline-somatic interactions over the lifetime of each tumor. We confirmed our findings by applying DGVar to germline WES from 398 patients from the Cancer Genome Atlas (TCGA). We performed extensive validation of our results in other UC cohorts and whole-exome sequencing data from more than 13,000 non-cancer subjects. Results DGVs were identified in 45/80 patients (56%) of the WCM UC cohort and 315 DGVs in 48% (190/398) of patients in the TCGA UC cohort. DGVs were significantly more common in UC patients of WCM and TCGA compared to 2,504 subjects from the 1000 genome project (1KGP) population (p Conclusions We show that close half of UC patients harbor DGVs, which potentially play a critical role in UC initiation and progression. Our results redefine the landscape of germline variants in urothelial cancer and provide a pivotal new understanding of their unique role in the biology of the disease.