Polymorphisms of XRCC1 gene, alcohol consumption and colorectal cancer

Abstract

To evaluate contribution of polymorphisms of the XRCC1 gene to the risk of colorectal cancer, we conducted a case-control study of 209 colorectal cancer cases and 209 age-and gender-matched controls in the Korean population. We tested the hypothesis by constructing allele combinations with known SNP. Allelic variants of the XRCC1 gene at codons 194, 280 and 399 were analyzed in lymphocyte DNA by PCR-RFLP. We observed an increased risk of colorectal cancer associated with the 399Gln allele. The odds ratio (OR) was 1.61 (95% confidence interval [CI] 1.09-2.39) for the 399Gln allele. When combined allele-specific OR were calculated after estimating frequencies, 3 common allele combinations were found to be associated with an increased risk of colorectal cancer. The OR for the 194Trp-280Arg-399Arg was 1.48 (95% CI 5 1.06-2.07) using 194Arg-280Arg-399Arg as the reference. The OR for the 194Arg-280His-399Arg and the 194Arg-280Arg-399Gln were 1.78 (95% CI 5 1.09-2.89) and 1.78 (95% CI 5 1.23-2.59), respectively. Analysis after controlling for smoking, exercise and dietary habits indicated that alcohol consumption ( 80 g/week) is a significant risk factor of colorectal cancer (OR 5 2.60, 95% CI 5 1. 46-4.62). An increased risk for colorectal cancer was identified in alcohol drinkers with the risky allele combinations. Our results suggest that polymorphisms in the XRCC1 genes may contribute to colorectal cancer susceptibility, and some evidence was obtained of a genetic modification for the relationship between alcohol intake and colorectal cancer. ' 2005 Wiley-Liss, Inc.Key words: polymorphisms; XRCC1; genotype; allele; colorectal cancer; alcohol Colorectal cancer is one of the most commonly diagnosed cancers in North America and Western Europe, 1 and is the fourth most common cause of cancer in South Korea. 2 Inherited deficiencies in DNA repair have been associated with an individual's susceptibility to cancer. 3 Therefore, polymorphisms of DNA repair genes may increase the risk of colorectal cancer.The human XRCC1 gene, one of the DNA repair genes, was identified because of its ability to restore DNA repair activity in a Chinese hamster ovary mutant cell line EM9. 4 The XRCC1 protein is involved in base-excision repair, and interacts with DNA ligase III, DNA polymerase b, poly(ADP-ribose)polymerase (PARP), polynucleotide kinase and AP endonuclease I. 5-8 The base-excision repair pathway is designed to remove non-bulky base adducts, which are produced by methylation, oxidation or reduction by ionizing radiation or oxidative damage. 9,10 Three coding polymorphisms of the DNA repair gene XRCC1 (Arg194Trp, Arg280His and Arg399Gln) have been identified in man, suggesting altered efficiency due to amino acid substitutions. 11,12 Alcohol consumption has been associated with the production of reactive oxygen species, which are known to cause DNA lesions that can be removed by the DNA base-excision repair pathway. 13 Meta-analyses of alcohol consumption in relation to colorectal cancer have reported a small or moderate addit...

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

“…In contrast with our finding of a nonstatistically significant inverse association between the XRCC1 codon 399 SNP and colorectal cancer risk, a previous study among Asians reported a positive association for this SNP (35), whereas another study among Asians (36) and two studies among Caucasians (31, 37) reported a null association. A study conducted in Egypt reported a positive association between both the codon 194 and 399 SNPs and colorectal cancer, but it was based on very small numbers (38).…”

Predictive Value of XRCC1 and XRCC3 Gene Polymorphisms for Risk of Ovarian Cancer Death After Chemotherapy

“…Most studies report a reduced risk of cancer associated with the 194Trp allele (Goode et al, 2002). The 399 polymorphism have been associated with a number of cancers, although results have been inconsistent (Abdel-Rahman et al, 2000;Goode et al, 2002;Mort et al, 2003;Nexo et al, 2003;Vogel et al, 2004;Hong et al, 2005;Yeh et al, 2005). Few studies have investigated the association between the XRCC1 280His allele and risk of cancer.…”

“…Few studies have investigated the association between the XRCC1 280His allele and risk of cancer. No association has been observed with colorectal cancer (Hong et al, 2005), but an increased risk has been reported with lung cancer (Ratnasinghe et al, 2001) and breast cancer (Moullan et al, 2003).…”

Ancillary risk information and pharmacogenetic tests: social and policy implications

“…[20][21][22][23] Several of the variants may provide ancillary risk information about various types of cancer (XRCC1, GSTM1, GSTP1, MTHFR, CYP2C9), many amenable to early detection and surveillance interventions that improve health outcomes. 20,[24][25][26] Based on these findings, we determined that the policy implications of ancillary information would be highly dependent on the characteristics of the individual tests: the strength of the risk estimate, the severity and potential for stigma of the associated disease, and the treatability of the disease. Tests whose associated disease risk are of high risk, are more severe or life-threatening or stigmatizing, and These categories do not include a consideration of the number or proportion of negative studies.…”