Comprehensive pathway-based interrogation of genetic variations in the nucleotide excision DNA repair pathway and risk of bladder cancer

Authors

  • Jinliang Xing MD, PhD,

    1. State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an, People's Republic of China
    2. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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  • Colin P. Dinney MD,

    1. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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  • Sanjay Shete PhD,

    1. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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  • Maosheng Huang MD,

    1. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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  • Michelle A. Hildebrandt PhD,

    1. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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  • Zhinan Chen MD, PhD,

    1. State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an, People's Republic of China
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    • The last 2 authors contributed equally to this article.

  • Jian Gu PhD

    Corresponding author
    1. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
    • Department of Epidemiology, Unit 1340, The University of Texas MD Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030

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    • The last 2 authors contributed equally to this article.

    • Fax: (713) 792-4657


Abstract

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. Cancer 2012;. © 2011 American Cancer Society.

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