Montserrat García-Closas 1 , * , Núria Malats 2 , Francisco X Real 3 , 4 , Meredith Yeager 5 , Robert Welch 5 , Debra Silverman 1 , Manolis Kogevinas 2 , 6 , Mustafa Dosemeci 1 , Jonine Figueroa 1 , Nilanjan Chatterjee 1 , Adonina Tardón 7 , Consol Serra 8 , Alfredo Carrato 9 , Reina García-Closas 10 , Cristiane Murta-Nascimento 2 , 3 , Nathaniel Rothman 1 , Stephen J Chanock 1 , 5
23 February 2007
Common genetic variation could alter the risk for developing bladder cancer. We conducted a large-scale evaluation of single nucleotide polymorphisms (SNPs) in candidate genes for cancer to identify common variants that influence bladder cancer risk. An Illumina GoldenGate assay was used to genotype 1,433 SNPs within or near 386 genes in 1,086 cases and 1,033 controls in Spain. The most significant finding was in the 5′ UTR of VEGF (rs25648, p for likelihood ratio test, 2 degrees of freedom = 1 × 10 −5). To further investigate the region, we analyzed 29 additional SNPs in VEGF, selected to saturate the promoter and 5′ UTR and to tag common genetic variation in this gene. Three additional SNPs in the promoter region (rs833052, rs1109324, and rs1547651) were associated with increased risk for bladder cancer: odds ratio (95% confidence interval): 2.52 (1.06–5.97), 2.74 (1.26–5.98), and 3.02 (1.36–6.63), respectively; and a polymorphism in intron 2 (rs3024994) was associated with reduced risk: 0.65 (0.46–0.91). Two of the promoter SNPs and the intron 2 SNP showed linkage disequilibrium with rs25648. Haplotype analyses revealed three blocks of linkage disequilibrium with significant associations for two blocks including the promoter and 5′ UTR (global p = 0.02 and 0.009, respectively). These findings are biologically plausible since VEGF is critical in angiogenesis, which is important for tumor growth, its elevated expression in bladder tumors correlates with tumor progression, and specific 5′ UTR haplotypes have been shown to influence promoter activity. Associations between bladder cancer risk and other genes in this report were not robust based on false discovery rate calculations. In conclusion, this large-scale evaluation of candidate cancer genes has identified common genetic variants in the regulatory regions of VEGF that could be associated with bladder cancer risk.
This article reports findings from a large-scale evaluation of common variation in candidate genes for cancer to identify variants that influence bladder cancer risk. We first evaluated 1,433 common variants within or near 386 genes in a large case-control study in Spain. The most significant finding was the gene coding for the vascular endothelial growth factor (VEGF). To further investigate this finding, we identified markers that captured most common variation in the whole gene. Analyses indicated that variants in regulatory regions of VEGF could modify the risk for developing bladder cancer. This association is biologically plausible since VEGF is critical for the growth of new blood vessels, which is important for tumor development, and its elevated expression in bladder tumors correlates with tumor progression. Future studies are required to confirm these findings, as well as to investigate the mechanisms for the observed associations.