Abstract
Simple SummaryThe objectives of this study were to identify rare germline variant associations in urothelial carcinoma of the bladder (UC) incidence and to determine its association with clinical outcomes. Our analysis reveals that individuals with MR1 rare germline variants had significantly worse OS than those without any, and those with ADGRL2 variants were slightly more likely to have UC compared to a control cohort matched for age, sex, and smoking status. These associations, using models incorporating known environmental covariates and using well-defined clinical phenotypes, highlight several candidates for prognostic indicator genes for the differential presentation of UC. These associations highlight several candidate genes that have the potential to explain clinical disparities in UC and predict UC outcomes.Urothelial carcinoma of the bladder (UC) is the fifth most common cancer in the United States. Germline variants, especially rare germline variants, may account for a portion of the disparity seen among patients in terms of UC incidence, presentation, and outcomes. The objectives of this study were to identify rare germline variant associations in UC incidence and to determine its association with clinical outcomes. Using exome sequencing data from the DiscovEHR UC cohort (n = 446), a European-ancestry, North American population, the complex influence of germline variants on known clinical phenotypes were analyzed using dispersion and burden metrics with regression tests. Outcomes measured were derived from the electronic health record (EHR) and included UC incidence, age at diagnosis, and overall survival (OS). Consequently, key rare variant association genes were implicated in MR1 and ADGRL2. The Kaplan–Meier survival analysis reveals that individuals with MR1 germline variants had significantly worse OS than those without any (log-rank p-value = 3.46 × 10−7). Those with ADGRL2 variants were found to be slightly more likely to have UC compared to a matched control cohort (FDR q-value = 0.116). These associations highlight several candidate genes that have the potential to explain clinical disparities in UC and predict UC outcomes.
Highlights
Urothelial carcinoma (UC) is the 5th most common cancer in the United States and is associated with a combination of genetic, environmental, and lifestyle factors [1,2]
The median age of the 446 UC patients in DiscovEHR was 69.5 years, 20.9% were women, and 67.7% were smokers, in line with the overall UC cohort of Geisinger [22]. 100% of the cohort identified as White, and this was reconfirmed genetically, with every member of the UC cohort mapping to the “Utah residents of European Ancestry” (CEU) population or “Toscana Italians” (TSI) population or both
While many possible reasons for these disparities exist ranging from referral patterns to hormonal milieu, limited data exist on the role of sex-based germline genetic differences
Summary
Urothelial carcinoma (UC) is the 5th most common cancer in the United States and is associated with a combination of genetic, environmental, and lifestyle factors [1,2]. Due to their low frequency and individually small contributions to the heritability of disease, are often not detectable even by extensive population association studies; they have been found to be associated with extreme outliers of gene expression [4]. Such germline variants, which account for a larger share of pathogenic variants and contribute to a greater share of extreme gene expression across human tissues, can have critical roles in influencing complex diseases and phenotypes such as differential response to drug treatment, platelet counts, and corresponding somatic mutations in tumor tissue [5,6,7]. Within the UC cohort, we used burden-based association tests to correlate the burden of rare variants in certain genes with pathologic characteristics and clinical outcomes, including OS
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