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.
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 (Arg(194)Trp and Arg(399)Gln), PARP (Val(762)Ala, Lys(940)Arg), XPD (Asp(312)Asn, Lys(751)Gln), OGG1 (Ser(326)Cys), and MGMT (Leu(84)Phe). 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 Arg(194)-Gln(399) haplotype was OR=0.7 (95% CI, 0.4-1.1), whereas, among carriers of the Trp(194)-Arg(399) 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.
Stern
Mariana C
MC
Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Room 5421A, Los Angeles, CA 90089, USA. stern_m@ccnt.usc.edu
Conti
David V
DV
Siegmund
Kimberly D
KD
Corral
Román
R
Yuan
Jian-Min
JM
Koh
Woon-Puay
WP
Yu
Mimi C
MC
D000368:Aged; D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D012846:Singapore; D012907:Smoking / Q000235:genetics* / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1
D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human