XRCC1, XRCC3, and XPD Polymorphisms as Modifiers of the Effect of Smoking and Alcohol on Colorectal Adenoma Risk

Abstract

Using a sigmoidoscopy-based case-control study (753 cases, 799 controls) in Los Angeles County, we investigated the potential modifier role in the effect of alcohol and smoking of single-nucleotide polymorphisms (SNP) in three DNA repair genes, XRCC1 (Arg194Trp and Arg399Gln), XRCC3 (Thr241Met), and XPD (Lys751Gln). We have previously reported an inverse association between the XRCC1 codon 399 SNP and adenoma risk among these subjects. We now report that subjects with the XPD Gln/Gln genotype were inversely associated with adenoma risk [odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-1.0] when compared with subjects with the Lys/Lys and Lys/Gln genotypes combined. This association differed between different ethnic groups (gene  race heterogeneity likelihood ratio test, P = 0.009), with a stronger inverse association among Latinos (OR, 0.1; 95% CI, 0.01-0.5) than among non-Latinos (OR, 0.9; 95% CI, 0.-1.3). We found no evidence of an XRCC3  smoking or alcohol interaction or an XRCC1  alcohol interaction. Instead, our data supported an XRCC1  smoking interaction (P = 0.048). Whereas XPD did not modify the effect of smoking, our data suggested an XPD  alcohol interaction. Analyses ignoring XPD showed no association between alcohol intake and adenoma prevalence; however, among carriers of the codon 751 Gln/Gln genotype, we found a significant positive association (OR, 2.5; 95% CI, 1.2-5.2 for ever drinkers; test of interaction P = 0.04). Our data suggest that the effects of smoking and alcohol may vary depending on the genetic background of proteins that participate in the base excision repair and nucleotide excision repair pathways. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2384-90)

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

“…Therefore, the results observed in this study might be driven by this SNP, which was not investigated. A causal role of the codon 280 SNP and differences in LD patterns between Singapore Chinese and U.S. subjects also could explain the discrepant findings between the present study and our previous adenoma study in Los Angeles (41). An interaction effect between XRCC1 genotype and smoking or alcohol on colorectal cancer risk is biologically plausible.…”

“…In contrast, a recent review of the literature concluded that the effect of smoking on risk of cancer might be modified by the XRCC1 genotype (40). Recently, we reported an XRCC1 genotype  smoking interaction effect on risk of colorectal adenomas in a Los Angeles sigmoidoscopybased study; the smoking effect was noted only among carriers of the Arg 194 -Arg 399 haplotype (41). Phenotype association studies suggest that both the XRCC1 codon 194 Trp and codon 399 Arg alleles are associated with higher repair proficiency (40), although functional studies have failed to find an effect for either SNP (42,43).…”

“…Several reports suggest that the codon 751 Gln allele might be associated with lower repair proficiency of damage induced by UV and chemical carcinogens, although other studies suggest this allele might confer higher repair proficiency of damage induced by ionizing radiation (45), suggesting a differential effect for this variant on XPD protein function under different exposures. Previously, we reported some evidence for an XPD Â alcohol interaction and no evidence of an XPD Â smoking interaction among colorectal adenomas, precursors of colorectal cancer, among a multiethnic sigmoidoscopy study in Los Angeles county (41). This is in contrast with another study that reported evidence of an XPD Â smoking interaction among hyperplastic and adenomatous polyps, when considering the codon 312 and codon 751 polymorphisms combined but no evidence of an XPD Â alcohol interaction (46), and a study that reported no evidence of an XPD Â smoking interaction (47) also among colorectal adenomas.…”

Polymorphism of XRCC1 predicts overall survival of gastric cancer patients receiving oxaliplatin-based chemotherapy in Chinese population

“…13 An SNP in codon 399 was considered to be related to the DNA repair and was likely to exhibit an effect on the protein function. 14 Several studies have reported the association of XRCC1-399 with the risk in non-small-cell lung cancer (NSCLC), 15 colorectal cancer, 16 gastric cancer 17 and prostate cancer. 18 Additionally, reports in colorectal cancer patients show an improved survival for patients with XRCC1-399 G allele receiving 5-FU/oxaplatin chemotherapy.…”

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

“…The XRCC3 protein interacts with Rad51-related proteins in the process of homologous recombination. The C18067T (Thr241Met) variant of the XRCC3 gene in exon 7 modulates its function and is linked to an increased risk of bladder, breast, colorectal, lung and skin cancer [37][38][39][40][41]. Rad51 plays a crucial role in the HR pathway.…”