DNA repair gene polymorphisms and tobacco smoking in the risk for colorectal adenomas

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-7236, USA.
Carcinogenesis (Impact Factor: 5.33). 06/2011; 32(6):882-7. DOI: 10.1093/carcin/bgr071
Source: PubMed


DNA damage is thought to play a critical role in the development of colorectal adenoma. Variation in DNA repair genes may
alter their capacity to correct endogenous and exogenous DNA damage. We explored the association between common single-nucleotide
polymorphisms (SNPs) in DNA repair genes and adenoma risk with a case–control study nested in the Prostate, Lung, Colorectal
and Ovarian Cancer Screening Trial. A total of 1338 left sided, advanced colorectal adenoma cases and 1503 matched controls
free of left-sided polyps were included in the study. Using DNA extracted from blood, 3144 tag SNPs in 149 DNA repair genes
were successfully genotyped. Among Caucasians, 30 SNPs were associated with adenoma risk at P < 0.01, with four SNPs remaining significant after gene-based adjustment for multiple testing. The most significant finding
was for a non-synonymous SNP (rs9350) in Exonuclease-1 (EXO1) [odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.11–1.51, P = 0.001)], which was predicted to be damaging using bioinformatics methods. However, the association was limited to smokers
with a strong risk for current smokers (OR = 2.15, 95% CI = 1.27–3.65) and an intermediate risk for former smokers (OR = 1.45,
95% CI = 1.14–1.82) and no association for never smokers (OR = 0.98, 95% CI = 0.76–1.25) (Pinteraction = 0.002). Among the top findings, an SNP (rs17503908) in ataxia telangiectasia mutated (ATM) was inversely related to adenoma risk (OR = 0.75, 95% CI = 0.63–0.91). The association was restricted to never smokers (OR
= 0.55, 95% CI = 0.40–0.76) with no increased risk observed among smokers (OR = 0.89, 95% CI = 0.70–1.13) (Pinteraction = 0.006). This large comprehensive study, which evaluated all presently known DNA repair genes, suggests that polymorphisms
in EXO1 and ATM may be associated with risk for advanced colorectal adenoma with the associations modified by tobacco-smoking status.

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Available from: Neil Caporaso, Aug 21, 2014
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    • "Caucasian US Nested case–control within screening arm of PLCO (Gao et al, 2011) Age ESCC 1027 1452 Asian China Neighborhood-based case–control from the UGI Cancer Genetics Project (Gao et al, 2009) and nested case–control from NITs (Blot et al, 1993) "
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