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

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 x 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.

• Authors: Xifeng Wu, Yuanqing Ye, Lambertus A Kiemeney, Patrick Sulem, Thorunn Rafnar, Giuseppe Matullo, Daniela Seminara, Teruhiko Yoshida, Norihisa Saeki, Angeline S Andrew, Colin P Dinney, Bogdan Czerniak, Zuo-feng Zhang, Anne E Kiltie, D Timothy Bishop, Paolo Vineis, Stefano Porru, Frank Buntinx, Eliane Kellen, Maurice P Zeegers, Rajiv Kumar, Peter Rudnai, Eugene Gurzau, Kvetoslava Koppova, Jose Ignacio Mayordomo, Manuel Sanchez, Berta Saez, Annika Lindblom, Petra de Verdier, Gunnar Steineck, Gordon B Mills, Alan Schned, Simonetta Guarrera, Silvia Polidoro, Shen-Chih Chang, Jie Lin, David W Chang, Katherine S Hale, Tadeusz Majewski, H Barton Grossman, Steinunn Thorlacius, Unnur Thorsteinsdottir, Katja K H Aben, J Alfred Witjes, Kari Stefansson, Christopher I Amos, Margaret R Karagas, Jian Gu
• Journal: Nature genetics (Nat Genet) Vol. 41 Issue 9 Pg. 991-5 (Sep 2009) ISSN: 1546-1718 [Electronic] United States
• PMID: 19648920 (Publication Type: Letter, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• GPI-Linked Proteins
• Membrane Glycoproteins
• Neoplasm Proteins
• PSCA protein, human

Topics

• Alleles
• Antigens, Neoplasm (genetics, immunology)
• Case-Control Studies
• Chromosome Mapping
• Chromosomes, Human, Pair 8
• GPI-Linked Proteins
• Gene Frequency
• Genes, Reporter
• Genetic Predisposition to Disease
• Genetic Variation
• Genome-Wide Association Study
• Haplotypes
• Heterozygote
• Homozygote
• Humans
• Linkage Disequilibrium
• Logistic Models
• Male
• Membrane Glycoproteins (genetics)
• Multivariate Analysis
• Mutation, Missense
• Neoplasm Proteins (genetics)
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Reproducibility of Results
• Urinary Bladder Neoplasms (genetics, immunology)