Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer

• Published in: Nature genetics Vol. 41; no. 9; pp. 991 - 995
• Main Authors: Wu, Xifeng, Ye, Yuanqing, Kiemeney, Lambertus A, Sulem, Patrick, Rafnar, Thorunn, Matullo, Giuseppe, Seminara, Daniela, Yoshida, Teruhiko, Saeki, Norihisa, Andrew, Angeline S, Dinney, Colin P, Czerniak, Bogdan, Zhang, Zuo-feng, Kiltie, Anne E, Bishop, D Timothy, Vineis, Paolo, Porru, Stefano, Buntinx, Frank, Kellen, Eliane, Zeegers, Maurice P, Kumar, Rajiv, Rudnai, Peter, Gurzau, Eugene, Koppova, Kvetoslava, Mayordomo, Jose Ignacio, Sanchez, Manuel, Saez, Berta, Lindblom, Annika, de Verdier, Petra, Steineck, Gunnar, Mills, Gordon B, Schned, Alan, Guarrera, Simonetta, Polidoro, Silvia, Chang, Shen-Chih, Lin, Jie, Chang, David W, Hale, Katherine S, Majewski, Tadeusz, Grossman, H Barton, Thorlacius, Steinunn, Thorsteinsdottir, Unnur, Aben, Katja K H, Witjes, J Alfred, Stefansson, Kari, Amos, Christopher I, Karagas, Margaret R, Gu, Jian
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2009; Nature Publishing Group
• Subjects: Agriculture; Alleles; Amino acids; Animal Genetics and Genomics; Antigens; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bladder; Bladder cancer; Cancer; Cancer and Oncology; Cancer och onkologi; Cancer Research; Case-Control Studies; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 8; Disease susceptibility; Fundamental and applied biological sciences. Psychology; Gene Frequency; Gene Function; Genes; Genes, Reporter; Genetic; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic research; Genetic Variation; genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; GPI-Linked Proteins; Haplotypes; Heterozygote; Homozygote; Human; Human Genetics; Humans; immunology; letter; Linkage Disequilibrium; Logistic Models; Male; Medical sciences; Membrane Glycoproteins; Membrane Glycoproteins - genetics; Missense; Multivariate Analysis; Mutation; Mutation, Missense; Neoplasm; Neoplasm Proteins; Neoplasm Proteins - genetics; Nephrology. Urinary tract diseases; Pair 8; Polymorphism; Polymorphism, Single Nucleotide; Population genetics; Promoter Regions; Promoter Regions, Genetic; Protein folding; Regression analysis; Reporter; Reproducibility of Results; Risk factors; Single Nucleotide; Single nucleotide polymorphisms; Smoking; Stem cells; Studies; Tumors of the urinary system; Urinary bladder; Urinary Bladder Neoplasms; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - immunology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; United States; United Kingdom; Urinary system disease; Genetic variability; Stem cell; Genetic variant; Urinary tract disease; Malignant tumor; Bladder cancer; Antigen; Gene; Bladder disease; Urogenital system; Prostate; Cancer
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.421

Xifeng Wu and colleagues show that a common variant in the prostate stem cell antigen ( PSCA ) gene on 8q24 is associated with susceptibility to urinary bladder cancer. The risk allele truncates the amino terminus of the PSCA gene product and reduces PSCA promoter activity in bladder cancer cell lines. 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.