Abstract
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.
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Change history
23 August 2009
In the version of this article initially published online, Simonetta Guarrera and Silvia Polidoro were inadvertently omitted from the author list, and an affiliation was omitted for Paolo Vineis. These errors have been corrected in all versions of this article.
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Acknowledgements
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.
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Contributions
Texas: X.W. conceived this study and established the M.D. Anderson bladder cancer study, supervised laboratory and statistical analyses and wrote the initial draft of the manuscript. Y.Y. supervised and performed statistical analyses. C.P.D., B.C. and H.B.G. were involved in patient recruitment. J.L. was involved in epidemiologic data collection and database management. D.W.C performed in vitro assays. T.M., G.B.M. and K.S.H. were involved in the validation genotyping. C.I.A. provided guidance in statistical analyses, assisted in the initial development of the research and contributed in manuscript preparation. J.G. was involved in the development of the research and study design, oversaw genotyping and in vitro assays and wrote the initial draft of the manuscript.
Other sites: L.A.K. and T.R. organized and supervised the replication efforts in European populations. P.S. performed primary statistical analysis of European populations. G.M., A.E.K., D.T.B., P.V., S. Porru, F.B., E.K., M.P.Z., R.K., P.R., E.G., K.K., J.I.M., M.S., B.S., A.L., P.d.V., G.S., S.G., S. Polidoro, S.T., U.T., K.K.H.A., J.A.W. and K.S. were involved in the subject ascertainment, DNA collection or data collection of European populations. A.S.A., A.S., Z.-f.Z. and S.-C.C. were involved in the subject ascertainment, DNA collection or data collection of US populations. D.S. was involved in the study design and data interpretation. N.S. and T.Y. provided reporter constructs of PSCA promoters and were instrumental in studying and discussing the function of PSCA and rs2294008. M.R.K. assisted in the initial development of the research, established the New Hampshire bladder cancer case control study and contributed to manuscript preparation. All authors contributed to the final paper.
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Wu, X., Ye, Y., Kiemeney, L. et al. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat Genet 41, 991–995 (2009). https://doi.org/10.1038/ng.421
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DOI: https://doi.org/10.1038/ng.421
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