XRCC1 Gene Polymorphisms And Susceptibility To Developing Esophageal Cancer In Henan Han Population

Background and AimsX-ray repair cross complementing gene 1 is an important component of DNA base excision repair system. Some studies have shown that there were associations between DNA repair genes and cancer susceptibility. Codon 194 and codon 399 are the most important polymorphic locis of XRCC1 gene, and there are also some studies on codon 280 and codon -77 with cancer susceptibility. These four polymorphisms were located in the main structural domain of protein XRCC1, which may affect XRCC1 protein function and consequently influence DNA repair capacity, thus result in the individual's susceptibility to cancer. Currently, there are some reports about XRCC1 gene polymorphisms and the risk of esophageal cancer, but the results are not consistent.In order to further explore the association between the XRCC1 gene polymerphisms and esophageal cancer, we carried out this study as bellow.Part I:Meta analysis method was used to assess the results of previous studies comprehensively and quantitatively, and to explore the relationship between XRCC1 gene and the risk of esophageal cancer.Part II:We conductted a case-control study using molecular biological methods in order to explore the association between three polymorphisms in XRCC1 gene and the risk of esophageal cancer.ObjectiveTo explore the association between three polymorphisms of XRCC1 gene and esophageal cancer, gene-environment interaction and esophageal cancer. In order to provide a theoretical basis for revealling the high-risk estimates, gene therapy and integrated control.MethodsAll case-control studies on association of XRCC1 codon 194 and 399 polymorphisms and the risk of esophageal cancer were obtained. Literatures were collectted comprehensively. Then all statistic analysis and heterogeneity test were performed using Rev Man4.2 and Stata8.0 softwares. And the meta-analysis was applied to calculate pooled OR value (with 95% CI) of EC. Stratified analysis was carried out by the pathological type and ethnic source.We conducted a case-control study in Han population from Henan province, and recruited 381 hospital based primary EC cases and 432 normal controls matching to cases by age and gender as objects. PCR-RFLP analysis was used to detect the genotype of XRCC1 gene 194,399 and -77 polymorphisms. Chi-square test and logistic regression were used to compare the distribution of the genotypes in three sites between case and control groups. SNPHAP software was used to detect haplotypes of XRCC1 three locis. Chi-square test was used to compare the distribution of haplotypes, combinded genotypes, trend analysis of the number of XRCC1 variations, trend analysis of the number of XRCC1 alleles between case and control groups. The interaction of three XRCC1 gene polymorphisms with smoking or drinking in the development of EC was also analysised.Results1. Meta analysisXRCC1 Arg194Trp:Compared with the wild-type homozygote CC, the pooled Odds Ratio (with 95% CI) of CT, TT and (CT+TT) genotype of XRCC1 codon 194 were 0.91(0.78,1.05),1.66(1.29,2.15),1.01(0.88,1.16), respectively. In a stratified analysis of pathological type, the risk of esophageal squamous cell carcinoma (ESCC) in XRCC1 codon 1 94Trp/Trp genotype increased 0.74-fold (OR:1.74, 95%CI:1.33,2.27) than Arg/Arg genotype. In a stratified analysis of ethnic source, the risk of EC in XRCC1 194Trp/Trp genotype increased 0.66-fold (OR:1.66,95%CI: 1.29,2.15) than Arg/Arg genotype in the Asian race.XRCC1 Arg399Gln:There was no statistically significant association of any genotype of XRCC1 Arg399Gln polymorphism with risk of EC.2. Case-control study2.1 XRCC1 gene polymorphism and the risk of esophageal cancerThere was no statistically significant association of any genotype of XRCC1 Arg194Trp or Arg399Gln polymorphisms with susceptibility of EC. Codon -77:Compared with the wild allele T, mutant allele C may be a protective factor for esophageal cancer susceptibility (OR:0.70,95% CI:0.48,1.00).2.2 Haplotype analysisThe haplotype CGT merged by wild-type alleles was taken as control haplotype, and the other six haplotypes were not associated with the risk of EC. Haplotype CGC may be a protective factor of esophageal cancer susceptibility.2.3 Combined genotypes analysisCompared with CC/GG/TT genotype combined by wild-type was used as control, the other sixteen combined genotypes were not associated with the risk of EC.2.4 Trend analysis of the number of mutationsThe genotypes with null mutations in the three sites were used as the control genotype, the genotypes with only one site mutation, two site mutations and three site mutations were not associated with the risk of EC(P>0.05).The genotypes with null mutation in the six alleles were used as the control genotype, the genotypes with one allele mutation, two or three allele mutations were not associated with the risk of EC (P>0.05).2.5 Gene-environment interaction:Compared with non-smoker and wild genotype, there was no interaction between smoking and variant genotypes of XRCC1 three sites in EC development. And there was no interaction between drinking and variant genotypes of XRCC1 three sites in EC development compared with non-drinking and wild genotype.Conclusion1. Meta AnalysisThe XRCC1194Trp/Trp genotype may increase the risk of esophageal squamous cell carcinoma (ESCC), and it was a risk factor of EC in the Asian race. There was no statistically significant association between any genotype of XRCC1 Arg399Gln polymorphism and the risk of EC.2. Case-control studyIt was showed that XRCC1 codon 194 and codon399 polymorphisms of XRCC1 gene may be not associate with the risk of EC in Han population from Henan province. Mutant allele C of XRCC1 codon -77 may be a protective factor for esophageal cancer susceptibility. Haplotype CGC may be a protective factor of esophageal cancer susceptibility. Interactions were not found between smoking or drinking and three polymorphisms for EC development in Han population from Henan province.