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DNA Repair Single-Nucleotide Polymorphisms in Colorectal Cancer and their Role as Modifiers of the Effect of Cigarette Smoking and Alcohol in the Singapore Chinese Health Study

¹ Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California; ² Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; and ³ The Cancer Center, University of Minnesota, Minneapolis, Minnesota

Requests for reprints: Mariana C. Stern, University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Room 5421A, Los Angeles, CA 90089. Phone: 323-865-0811; Fax: 323-865-0140. E-mail: stern_m{at}ccnt.usc.edu

Recently, we reported that among Singapore Chinese, cigarette smoking and alcohol drinking were independent risk factors for colorectal cancer. Both tobacco smoking and alcohol use are plausible colorectal cancer risk factors, partly due to their ability to induce mutations in the colorectal lumen. In the present study, we investigated the role in colorectal cancer of single-nucleotide polymorphisms in five DNA repair genes: XRCC1 (Arg¹⁹⁴Trp and Arg³⁹⁹Gln), PARP (Val⁷⁶²Ala, Lys⁹⁴⁰Arg), XPD (Asp³¹²Asn, Lys⁷⁵¹Gln), OGG1 (Ser³²⁶Cys), and MGMT (Leu⁸⁴Phe). We conducted this study within the Singapore Chinese Health Study, a population-based cohort of 63,257 middle-aged and older Singapore Chinese men and women enrolled between 1993 and 1998. Our study included 1,176 controls and 310 cases (180 colon and 130 rectum cancer). We observed a positive association between the PARP codon 940 Lys/Arg and Arg/Arg genotypes and colorectal cancer risk [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.1-3.1], and an inverse association between the MGMT codon 84 Leu/Phe or Phe/Phe genotypes and colon cancer risk (OR, 0.6; 95% CI, 0.3-0.9), but not rectal cancer (test of heterogeneity by tumor site, P = 0.027). We observed evidence that XRCC1 may modify the effects of smoking (interaction P = 0.012). The effect of smoking among carriers of the Arg¹⁹⁴-Gln³⁹⁹ haplotype was OR = 0.7 (95% CI, 0.4-1.1), whereas, among carriers of the Trp¹⁹⁴-Arg³⁹⁹ haplotype, it was OR = 1.6 (95% CI, 1.1-2.5). We also observed a nonstatistically significant modification of XRCC1 on the effects of alcohol (P = 0.245). Whereas alcohol had no effect among carriers of the codon 194 Arg/Arg (OR, 1.0; 95% CI, 0.6-1.7) or Arg/Trp genotypes (OR, 1.1; 95% CI, 0.6-1.9), there was a positive association among carriers of the Trp/Trp genotype (OR, 2.8; 95% CI, 1.0-8.1). Our results support a role for reactive oxygen species as relevant genotoxins that may account for the effects of both smoking and alcohol on colorectal cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2363–72)

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