Genetic Analysis Reveals Rare Variants in T-Cell Response Gene MR1 Associated with Poor Overall Survival after Urothelial Cancer Diagnosis

• Main Authors: Lisa Bang, Manu Shivakumar, Tullika Garg, Dokyoon Kim
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Cancers
• Subjects: rare variant analysis; electronic health record; biobank; bladder cancer
• Online Access: https://www.mdpi.com/2072-6694/13/8/1864

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 (<i>n</i> = 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 <i>MR1</i> and <i>ADGRL2.</i> The Kaplan–Meier survival analysis reveals that individuals with <i>MR1</i> germline variants had significantly worse OS than those without any (log-rank <i>p</i>-value = 3.46 × 10⁻⁷). Those with <i>ADGRL2</i> 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.