TY - JOUR
T1 - Comprehensive pathway-based interrogation of genetic variations in the nucleotide excision DNA repair pathway and risk of bladder cancer
AU - Xing, Jinliang
AU - Dinney, Colin P.
AU - Shete, Sanjay
AU - Huang, Maosheng
AU - Hildebrandt, Michelle A.
AU - Chen, Zhinan
AU - Gu, Jian
PY - 2012/1/1
Y1 - 2012/1/1
N2 - BACKGROUND: Growing evidence suggests that single nucleotide polymorphisms (SNPs) in nucleotide excision repair (NER) pathway genes play an important role in bladder cancer etiology. However, only a limited number of genes and variations in this pathway have been evaluated to date. METHODS: In this study, the authors applied a comprehensive pathway-based approach to assess the effects of 207 tagging and potentially functional SNPs in 26 NER genes on bladder cancer risk using a large case-control study that included 803 bladder cancer cases and 803 controls. RESULTS: In total, 17 SNPs were associated significantly with altered bladder cancer risk (P <.05), of which, 7 SNPs retained noteworthiness after they were assessed with a Bayesian approach for the probability of false discovery. The most noteworthy SNP was reference SNP 11132186 (rs11132186) in the inhibitor of growth family, member 2 (ING2) gene. Compared with the major allele-containing genotypes, the odds ratio was 0.52 (95% confidence interval, 0.32-0.83; P =.005) for the homozygous variant genotype. Three additional ING2 variants also exhibited significant associations with bladder cancer risk. Significant gene-smoking interactions were observed for 3 of the top 17 SNPs. Furthermore, through an exploratory classification and regression tree (CART) analysis, potential gene-gene interactions were identified. CONCLUSIONS: In this a large association study of the NER pathway and the risk of bladder cancer, several novel predisposition variants were identified along with potential gene-gene and gene-environment interactions in modulating bladder cancer risk. The results reinforce the importance of a comprehensive, pathway-focused, and tagging SNP-based candidate gene approach to identify low-penetrance cancer susceptibility loci.
AB - BACKGROUND: Growing evidence suggests that single nucleotide polymorphisms (SNPs) in nucleotide excision repair (NER) pathway genes play an important role in bladder cancer etiology. However, only a limited number of genes and variations in this pathway have been evaluated to date. METHODS: In this study, the authors applied a comprehensive pathway-based approach to assess the effects of 207 tagging and potentially functional SNPs in 26 NER genes on bladder cancer risk using a large case-control study that included 803 bladder cancer cases and 803 controls. RESULTS: In total, 17 SNPs were associated significantly with altered bladder cancer risk (P <.05), of which, 7 SNPs retained noteworthiness after they were assessed with a Bayesian approach for the probability of false discovery. The most noteworthy SNP was reference SNP 11132186 (rs11132186) in the inhibitor of growth family, member 2 (ING2) gene. Compared with the major allele-containing genotypes, the odds ratio was 0.52 (95% confidence interval, 0.32-0.83; P =.005) for the homozygous variant genotype. Three additional ING2 variants also exhibited significant associations with bladder cancer risk. Significant gene-smoking interactions were observed for 3 of the top 17 SNPs. Furthermore, through an exploratory classification and regression tree (CART) analysis, potential gene-gene interactions were identified. CONCLUSIONS: In this a large association study of the NER pathway and the risk of bladder cancer, several novel predisposition variants were identified along with potential gene-gene and gene-environment interactions in modulating bladder cancer risk. The results reinforce the importance of a comprehensive, pathway-focused, and tagging SNP-based candidate gene approach to identify low-penetrance cancer susceptibility loci.
KW - SNP
KW - bladder cancer
KW - gene-smoking interaction
KW - genetic susceptibility
KW - nucleotide excision repair
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U2 - 10.1002/cncr.26224
DO - 10.1002/cncr.26224
M3 - Article
C2 - 21692063
AN - SCOPUS:83855160935
SN - 0008-543X
VL - 118
SP - 205
EP - 215
JO - Cancer
JF - Cancer
IS - 1
ER -