Large-Scale Evaluation of Candidate Genes Identifies Associations between VEGF Polymorphisms and Bladder Cancer Risk

Abstract

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.

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

“…The studies of Garcia-Closas et al and Shen et al revealed an association between the risk of cancer and a single XPC polymorphism, namely: between 33512C and the risk of bladder cancer, as well as the PAT+ polymorphism in intron 9 and the risk of squamous cell carcinoma of head and neck [55,56]. However, taking into account the high LD between these XPC variants, it remains to be determined whether a single polymorphism or their association is of most importance in the modulation of cancer risk.…”

Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab

“…Median number of treatment cycles administered was 7 (range, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Dose reduction (>25% of the planned dose for any of the drug for two or more cycles) or treatment delay (>1 week of delay for two or more cycles) was necessary in eight patients (20%).…”

“…Previous studies have demonstrated that the presence of VEGF single nucleotide polymorphisms (SNPs) in the promoter and 5' untranslated region (UTR) regions may be a risk factor for prostate and bladder cancer development [9,10]. Moreover, VEGF SNPs may have a prognostic value for non-small cell lung, colorectal, ovarian, and breast cancer patients [11][12][13][14].…”

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704

“…An Illumina GoldenGate assay (Illumina, San Diego, CA, USA) was used to genotype the CDA polymorphism. 9,10 This technology has a concordance, reproducibility and call rate 499.5%. CDA Lys 27 Gln polymorphism genotyping has three potential results: most frequent homozygous (homozygote wild-type reference, Lys/Lys), heterozygous (Lys/Gln) and least common homozygous (homozgote variant, Gln/Gln).…”