Abstract P038: Transcriptome-wide association study identifies novel genes associated with bladder cancer risk
Authors: Li Siting , Gui Jiang , Karagas Margaret R. , Passarelli Michael N. 
Published: January 2023

Background: Genome-wide association studies (GWAS) have identified several common germline variants associated with bladder cancer risk. However, the genetic architecture of bladder cancer risk is still largely unknown. Therefore, we conducted a transcriptome-wide association study (TWAS) to identify gene expression patterns associated with bladder cancer risk. Methods: Individual-level genotype data from bladder cancer cases and controls was accessed from dbGaP (phs000346.v2.p2). We included 3,630 muscle invasive and non-muscle invasive bladder cancer cases and 3,356 controls from the Spanish Bladder Cancer Study (1,145 cases and 1,083 controls) and the New England Bladder Cancer Study (Maine and Vermont, 2,485 cases and 2,273 controls) with imputed genotype data for 22 million single-nucleotide polymorphisms (SNPs). We used PrediXcan to predict gene expression in whole blood using reference data from the Depression Genes and Networks (DGN). Covariate-adjusted logistic regression was used to estimate the associations between gene expression and bladder cancer risk. Results were validated using data from 280 non-muscle invasive bladder cancer cases and 353 controls of the New Hampshire Bladder Cancer Study. Results: We identified five genes associated with bladder cancer risk, including a previously reported locus (1p13.3: GSTM1) and four other loci (4p16.3: FAM53A, 7q22.3: RP11-325F22.2, 8p23.1: RP11-297N6.4, 11q24.1: JHY). Among them, higher predicted expression of GSTM1 in whole blood was associated with lower risk of bladder cancer (Discovery dataset OR = 0.78, 95% CI = 0.67, 0.92; Validation dataset OR = 0.58, 95% CI = 0.34, 0.98). Higher predicted expression of FAM53A (Discovery OR = 1.34, 95% CI = 1.08, 1.68; Validation OR = 3.79, 95% CI = 1.76, 8.29), RP11-325F22.2 (Discovery OR = 1.34, 95% CI = 1.09, 1.65; Validation OR = 2.11, 95% CI = 1.05, 4.30), RP11-297N6.4 (Discovery OR = 1.78, 95% CI = 1.22, 2.60; Validation OR = 6.32, 95% CI = 1.74, 23.34) and JHY (Discovery OR = 1.94, 95% CI = 1.30, 2.91; Validation OR = 6.78, 95% CI = 1.85, 25.76) in whole blood was associated with higher risk of bladder cancer. Conclusion: Our TWAS identified five genes associated with bladder cancer risk: GSTM1, a previously reported locus associated with bladder cancer risk, is related to metabolic detoxification. Four novel loci were identified: FAM53A (related to neural tube development and was previously reported to be related to breast cancer progression), JHY (related to axoneme structure), RP11-325F22.2 (lincRNA), and RP11-297N6.4 (lncRNA). These loci require further validation and may help to reveal the underlying mechanism of the relationship between gene expression and bladder cancer risk.

Citation Format: Siting Li, Jiang Gui, Margaret R. Karagas, Michael N. Passarelli. Transcriptome-wide association study identifies novel genes associated with bladder cancer risk. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P038.