Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk.

Montserrat García-Closas, Núria Malats, Francisco X. Real, Meredith Yeager, Robert Welch, Debra Silverman, Manolis Kogevinas, Mustafa Dosemeci, Jonine Figueroa, Nilanjan Chatterjee, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina García-Closas, Cristiane Murta-Nascimento, Nathaniel Rothman, Stephen J. Chanock

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
JournalPLoS Genetics
Volume3
Issue number2
DOIs
StatePublished - Feb 23 2007
Externally publishedYes

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Urinary Bladder Neoplasms
Vascular Endothelial Growth Factor A
single nucleotide polymorphism
Single Nucleotide Polymorphism
polymorphism
5' Untranslated Regions
5' untranslated regions
genetic polymorphism
promoter regions
gene
cancer
Genes
tumor
neoplasms
genes
Neoplasm Genes
Linkage Disequilibrium
linkage disequilibrium
Introns
Haplotypes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

García-Closas, M., Malats, N., Real, F. X., Yeager, M., Welch, R., Silverman, D., ... Chanock, S. J. (2007). Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk. PLoS Genetics, 3(2). https://doi.org/10.1371/journal.pgen.0030029

Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk. / García-Closas, Montserrat; Malats, Núria; Real, Francisco X.; Yeager, Meredith; Welch, Robert; Silverman, Debra; Kogevinas, Manolis; Dosemeci, Mustafa; Figueroa, Jonine; Chatterjee, Nilanjan; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Murta-Nascimento, Cristiane; Rothman, Nathaniel; Chanock, Stephen J.

In: PLoS Genetics, Vol. 3, No. 2, 23.02.2007.

Research output: Contribution to journalArticle

García-Closas, M, Malats, N, Real, FX, Yeager, M, Welch, R, Silverman, D, Kogevinas, M, Dosemeci, M, Figueroa, J, Chatterjee, N, Tardón, A, Serra, C, Carrato, A, García-Closas, R, Murta-Nascimento, C, Rothman, N & Chanock, SJ 2007, 'Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk.', PLoS Genetics, vol. 3, no. 2. https://doi.org/10.1371/journal.pgen.0030029
García-Closas, Montserrat ; Malats, Núria ; Real, Francisco X. ; Yeager, Meredith ; Welch, Robert ; Silverman, Debra ; Kogevinas, Manolis ; Dosemeci, Mustafa ; Figueroa, Jonine ; Chatterjee, Nilanjan ; Tardón, Adonina ; Serra, Consol ; Carrato, Alfredo ; García-Closas, Reina ; Murta-Nascimento, Cristiane ; Rothman, Nathaniel ; Chanock, Stephen J. / Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk. In: PLoS Genetics. 2007 ; Vol. 3, No. 2.
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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 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.",
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