Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk.
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 x 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.
García-Closas
Montserrat
M
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland, United States of America. montse@nih.gov
Malats
Núria
N
Real
Francisco X
FX
Yeager
Meredith
M
Welch
Robert
R
Silverman
Debra
D
Kogevinas
Manolis
M
Dosemeci
Mustafa
M
Figueroa
Jonine
J
Chatterjee
Nilanjan
N
Tardón
Adonina
A
Serra
Consol
C
Carrato
Alfredo
A
García-Closas
Reina
R
Murta-Nascimento
Cristiane
C
Rothman
Nathaniel
N
Chanock
Stephen J
SJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002277:Carcinoma / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012307:Risk Factors; D001749:Urinary Bladder Neoplasms / Q000209:etiology / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D042461:Vascular Endothelial Growth Factor A