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.
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.
Authors: Anne F Nichols; Toshiki Itoh; Francesca Zolezzi; Stephanie Hutsell; Stuart Linn Journal: Nucleic Acids Res Date: 2003-01-15 Impact factor: 16.971
Authors: M Nagashima; M Shiseki; K Miura; K Hagiwara; S P Linke; R Pedeux; X W Wang; J Yokota; K Riabowol; C C Harris Journal: Proc Natl Acad Sci U S A Date: 2001-07-31 Impact factor: 11.205
Authors: Or Gozani; Philip Karuman; David R Jones; Dmitri Ivanov; James Cha; Alexey A Lugovskoy; Cheryl L Baird; Hong Zhu; Seth J Field; Stephen L Lessnick; Jennifer Villasenor; Bharat Mehrotra; Jian Chen; Vikram R Rao; Joan S Brugge; Colin G Ferguson; Bernard Payrastre; David G Myszka; Lewis C Cantley; Gerhard Wagner; Nullin Divecha; Glenn D Prestwich; Junying Yuan Journal: Cell Date: 2003-07-11 Impact factor: 41.582
Authors: Johanne Bentley; Christine P Diggle; Patricia Harnden; Margaret A Knowles; Anne E Kiltie Journal: Nucleic Acids Res Date: 2004-10-05 Impact factor: 16.971
Authors: Roman Corral; Juan Pablo Lewinger; David Van Den Berg; Amit D Joshi; Jian-Min Yuan; Manuela Gago-Dominguez; Victoria K Cortessis; Malcolm C Pike; David V Conti; Duncan C Thomas; Christopher K Edlund; Yu-Tang Gao; Yong-Bing Xiang; Wei Zhang; Yu-Chen Su; Mariana C Stern Journal: Int J Cancer Date: 2014-01-13 Impact factor: 7.396