We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 × 10-10 and the allelic odds ratio was 1.15 (95% confidence interval 1.10-1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
Bibliographical noteFunding Information:
The study was partially supported by NIH grants U01 CA 127615 (X.W.), R01 CA 74880 (X.W.), P50 CA 91846 (X.W., C.P.D.), R01 CA 133996 (C.I.A), P42 ES07373 (M.R.K.) and R01 CA 57494 (M.R.K.), R01 CA 131335 (J.G.) and the Kleberg Center for Molecular Markers at MDACC. We thank the genotyping personnel, study coordinators and interviewers for performing experiments and recruiting participants. We are especially thankful for all the study participants who made the population-based research possible.