| Objective DNA damage repair genes have been proposed as candidate cancer susceptibility genes. The excision repair cross-complementing rodent repair deficiency, complementation group2(ERCC2)/x eroderma pigmentosum complementary group D (XPD) protein is considered to be a key enzyme in nucleotide excision repair (NER) pathway. Polymorphism of ERCC2can reduce the individual DNA damage repair capacity, may increase susceptibility to tumors. The association of functional SNPs in ERCC2gene Arg156Arg and Lys751Gln with esophageal cancer are commonly researched in many studies, but the results are not consistent. However, whether more common ERCC2variants are also associated with esophageal cancer susceptibility has not been investigated. Many studies have shown that, with a few genetic markers may keep the information of most of the haplotypes, namely the selection of some SNP sites as a tag SNP, these sites can be representative of the entire genome of all information, whether or not the SNPs themselves have a functional effect. The aim of this study is to explore the relationship of the tag SNPs of ERCC2selected from the International HapMap Project with the susceptibility to esophageal squamous cell carcinoma (ESCC) and the role of gene-gene and gene-environment interactions in the development of ESCC.Methods A frenquency matching case-control study including405patients with ESCC from a hospital and405population-based healthy controls was carried out in Henan population. Individual data were collected. The genotypes of three tag SNPs (rs3916874, rs238415, and rs1615836) and two functional SNPs (Asp312Asn and Lys751Gln) were detected by using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). X2test was used to compare the distribution differences of age, gender, family history, smoking, drinking and genotypes from each SNP between cases and controls. Hardy-Weinberg equilibrium test, allele frequencies, genotype frequencies, haplotype frequencies and LD were calculated using the Haploview4.2software. For each SNP, unconditional multivariate logistic regression was applied to calculate odds ratio (OR) and95%confidence interval (CI) adjusting for age. gender, family history, smoking and drinking. Gene-environment interactions were evaluated by using the non-parametric multifactor dimensionality reduction (MDR) software.Results We found that individuals carrying minor allele of Lys751Gln had an increased risk of esophageal cancer (OR:1.45,95%CI:1.06-1.99, P<0.05), and two ERCC2haplotypes were associated with risk of esophageal cancer. Haplotype5defined by rs3916874G-rs238415C-rsl618536G-Arg156ArgG-Lys751GlnC and haplotype7defined by rs3916874G-rs238415G-rs1618536A-Arg156ArgG-Lys751GlnC were strongly associated with an increased risk of esophageal cancer (OR:2.16,95%CI:1.27-3.51, P<0.0001for hap5; OR:3.72,95%CI:1.89-6.63, P<0.001for hap7). Haplotype analysis of tagging SNP, the result show that haplotype defined by GCG and GGA can increase risk of esophageal cancer (OR:1.46,95%CI:1.17-1.81; OR:1.46,95%CI:1.18-1.80). haplotype defined by GCA and GGG can reduce risk of esophageal cancer (OR:0.46,95%CI:0.31-0.68; OR:0.30,95%CI:0.21-0.44).Gene-environment interaction analysis by MDR software showed that three-factor-model including rs238415, rs1618536and family history of cancer with higher risk for esophageal cancer in an OR with a P value under0.0001(OR:3.23,95%CI:2.37-4.40).These results suggested that genetic variations in the ERCC2gene are associated with risk of esophageal cancer, and there are significantly synergy interaction between gene polymorphisms and family history.Conclusions The present study suggested that genetic variation (MAF>0.1) in the ERCC2gene is associated with risk of esophageal cancer, the results of haplotype analyses and SNP analyses also confirmed that allele C of Lys751Gln can increase risk of esophageal cancer,and there are significantly synergy interaction between gene polymorphisms and family history. |
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