Cancer Letters

Cancer Letters

Volume 216, Issue 2, 28 December 2004, Pages 157-164
Cancer Letters

Polymorphisms of XRCC1 and risk of esophageal and gastric cardia cancer

https://doi.org/10.1016/j.canlet.2004.03.012Get rights and content

Abstract

Background: Linxian, a rural county in North Central China, has among the highest rates of esophageal squamous cell carcinoma and gastric cardia adenocarcinoma in the world. In a nested case-cohort study that originated from two cancer prevention trials in Linxian, we examined the relationship between these cancers and two polymorphisms in the DNA repair gene XRCC1.

Methods: We conducted a case-cohort study among individuals in the cohort who were alive and cancer free in 1991, and had blood samples for DNA extraction. Real time Taqman analyses were conducted to genotype incident cancer cases (n=221, 131 esophageal and 90 gastric cardia cancer cases) that developed through May 1996, and on an age- and sex-matched reference cohort (n=454). We used Cox proportional hazard models to estimate relative risks (RR) and 95% confidence intervals (95% CI).

Results: We observed no association between the variant genotype in XRCC1 Arg194Trp (codon 194 arganine to tryptophan substitution) and esophageal or gastric cardia cancer. However, carrying at least one copy of the variant allele in XRCC1 Arg399Gln (codon 399 arganine to glutamine substitution) was associated with reduced risk of gastric cardia cancer (RR: 0.60, 95% CI: 0.37–0.97) and the combined category esophageal/gastric cancer (RR: 0.67, 95% CI: 0.48–0.95). In combined polymorphisms analyses, we observed a significant reduction in risk of combined esophageal/gastric cancer among individuals that had both the XRCC1 Arg194Trp and Arg399Gln variant genotyopes (RR: 0.47, 95% CI: 0.26–0.84).

Conclusions: Our results suggest that the XRCC1 Arg399Gln variant genotype is associated with reduced risk of upper GI cancer and that individuals with both XRCC1 variant genotypes are also at significantly reduced risk of upper GI cancer in this high-risk Chinese population.

Introduction

X-ray repair cross complementing group 1 (XRCC1) is one of the proteins involved in the repair of gaps in the restorative phase of base excision repair (BER). Other enzymes involved in BER include apurinic/apyrimidinic endonuclease (APE), polynucleotide kinase, DNA polymerase β and DNA ligase III [1], [2]. BER, nucleotide excision repair, mismatch repair and double strand break repair are pathways of DNA repair involved in maintaining genomic integrity against damage caused by endogenous and exogenous mutagens. Because of the importance of maintaining cellular genomic integrity, the many enzymes involved in complex DNA repair processes are thought to be candidate cancer-susceptibility genes.

Polymorphisms in DNA repair enzyme genes, which result in amino-acid substitutions, may alter the efficiency of DNA repair and influence cancer susceptibility [3], [4], [5], [6], [7], [8], [9]. The genetic polymorphism in the XRCC1 gene at codon 194 (XRCC1 Arg194Trp), which results in an arginine to tryptophan amino acid substitution, occurs at a conserved residue in humans, hamsters, and mice, and this evolutionary conservation suggests that this site is functionally important [10], [11]. The genetic polymorphism in the XRCC1 gene at codon 399 (XRCC1 Arg399Gln) results in an arginine to glutamine amino acid substitution. A report by Lunn and colleagues measured the prevalence of aflatoxin B1 adducts in placental DNA from 120 Taiwanese women and suggested that the XRCC1 Arg399Gln polymorphism may result in deficient DNA repair capacity [12]. A BCRT domain found in many proteins responsive to DNA damage with cell cycle checkpoint functions has also been identified in XRCC1 [13]. Because amino acid residues at the protein–protein interfaces of multi-protein complexes and residues involved in the active sites play a role in enzyme function, it is possible that XRCC1 polymorphisms result in altered DNA repair capacity.

Linxian, China, is a region where the rates of squamous esophageal/adenomatous gastric cardia cancer is more than 400 per 100,000 person-years [14] (approximately 100 times the rates in US whites [14]). Subjects for the current study were drawn from two randomized, placebo controlled intervention trials of nutritional supplements conducted between 1985 and 1991 in Linxian. Detailed results of these trials have been published elsewhere [15], [16], [17]. The primary objective of both Linxian trials was to test whether nutritional supplementation would reduce the rates of mortality from and incidence of esophageal and gastric cardia cancers. In the smaller of these two studies, the Dysplasia trial, a multivitamin containing selenium was randomly assigned to 3318 people with pre-existing esophageal dysplasia. At the end of the 6-year intervention, there was no statistically significant reductions esophageal or gastric cardia cancer mortality [16]. The larger trial referred to as the General Population Trial, with 29,584 participants tested four different combinations of nutrient supplements for 5.25 years. The group receiving the supplement with selenium, β-carotene, and vitamin E had a statistically significant reduction of mortality and incidence rates for esophageal/gastric cardia cancers (esophageal and gastric cardia cancers combined) by 10 and 6% compared to placebo, respectively [17]. Supplementation with selenium, β-carotene, and vitamin E had no effect on mortality and incidence rates of esophageal cancer or cardia cancer alone.

The goal of the present case-cohort study is to explore the association between the XRCC1 Arg194Trp and XRCC1 Arg399Gln polymorphisms and risk of incident esophageal and gastric cardia cancers.

Section snippets

Study population

The subjects for this study were selected from 4334 participants in the Dysplasia and General Population Nutrition Intervention Trials, who were alive and disease free at the time blood was collected in 1991 (Dysplasia=1532 (35.3%); Genpop=2802 (64.7%)). Individuals with >1.5 μg of DNA were considered eligible for participation in the case-cohort (n=4005). We used a stratified case-cohort design , , to select individuals for inclusion in this study from the cohorts. The case-cohort study

Results

Table 1 shows the distribution of case-cohort characteristics and the distribution of genotypes for each polymorphism by cancer status. The prevalence of the homozygous variant genotypes for both polymorphisms was low (<10%), limiting statistical power in this stratum to test for associations.

Table 2 gives the RR and 95% CI for the polymorphisms and cancer with the heterozygous and homozygous-variant categories combined to increase statistical power. There was no association between the XRCC1

Discussion

Esophageal squamous cell carcinoma is one of the most prevalent cancers in China and it has been postulated that carcinogens such as polycyclic aromatic hydrocarbons (PAHs), nutritional deficiencies and other environmental factors cause this disease [23]. In addition to esophageal cancer, the incidence of gastric cardia cancer is also quite high in China and a number of environmental factors including smoking, alcohol consumption and dietary practices have been postulated to influence risk of

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