Correlation Of XRCC2 And XRCC5 Polymorphisms To Risk Of ESCC And GCA In A High Incident Region Of Northern China

Objective: Both environmental carcinogen and product of metabolism may induce DNA damage, therefore, the biology mainly depend on a series of DNA repair pathways to maintain the genomic stability and integrity. DNA double strand break repair is an important pathway to repair DNA damage. DNA double strand break repair gene have high incidence of polymorphism. Polymorphism of DNA repair gene may lead to the difference of DNA repair capacity and influence an individual′s susceptibility to carcinogenesis. It was shown that DNA repair deficiency may be associated with the risk of developing cancer. This study was designed to investigate the correlation of single nucleotide polymorphisms (SNPs), C41657T and G4234C of XRCC2 gene, C74468A and G74582A of XRCC5 gene, to susceptibilities of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in a population of high incidence region of Hebei Province.Methods: This population-based case-control study included 579 cancer patients (327 with ESCC and 252 with GCA) and 614 healthy controls. Genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. Polymorphisms of XRCC2 and XRCC5 gene were analyzed by PCR-restriction fragment length polymorphism analysis (RFLP).Statistical analysis was performed using SPSS11.5 software package. P<0.05 was considered significant for all statistical analyses. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in study groups using Chi-square test. Comparison of the XRCC2 and XRCC5 genotype, allelotype and haplotype distribution in cancer patients and healthy controls was performed by means of two-sided contingency tables using Chi-square test. The XRCC2 and XRCC5 haplotype frequencies and linkage disequilibrium coefficient were estimated by using EH linkage software and 2LD software. The odds ratio (OR) and 95% confidence Interval (CI) were calculated using an unconditional logistic regression model and adjusted by age, gender, smoking status and family history of upper gastrointestinal cancer (UGIC) accordingly.Results1 The frequency of positive family history of upper gastrointestinal cancer (UGIC) in ESCC (48.0%) and GCA (48.4%) patients was significantly higher than that in healthy controls (35.2%) (χ2=14.69 and 13.15, P=0.00). Family history of UGIC may increase the risk of developing ESCC and GCA (age, gender and smoking status adjusted OR=1.70 and 1.73, 95%CI=1.30-2.24 and 1.29-2.33, respectively). 2 The distribution of XRCC2 SNPs genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (all P values are above 0.05). Frequency of the XRCC2 C41657T T allele in GCA patients was 22.4%, which was significantly higher than that in healthy controls (17.2%) (χ2=6.45,P=0.01). The distribution of C/T genotype in the overall GCA patients(36.1%) was significantly different from that in healthy controls(29.5%) (P<0.05). Frequency of the T/T genotype in ESCC(5.5%) was significantly higher than that in healthy controls(2.4%) (P<0.05). Compared with individuals with the C/C genotype, individuals with the C/T genotype or T allele(C/T+T/T genotype) had significantly higher risk to develop GCA and T/T genotype had significantly higher risk to develop ESCC (age, gender, smoking status and family history of UGIC adjusted OR=1.38, 1.40 and 2.14, 95%CI=1.02~1.90, 1.03~1.91 and 1.11~4.24, respectively). When stratified by smoking status, compared with individuals with the C/C genotype, individuals with the T/T genotype in smoker group had higher risk in developing ESCC and C/T genotype T allele(C/T+T/T genotype) in non-smoker group had higher risk in developing GCA (age, gender, family history of UGIC adjusted OR=2.65, 1.65 and 1.75, 95%CI=1.01~6.95 and 1.06~2.57, 1.14~2.68 respectively). When stratified by family history of UGIC, compared with individuals with C/C genotype, individuals with the T/T genotype in the group without family history of UGIC had higher risk in developing ESCC and GCA (age, gender, smoking status adjusted OR=3.03 and 3.20, 95%CI=1.17~7.88 and 1.10~9.29, respectively).3 The allelotype and genotype distributions of the XRCC2 G4234C SNP in the overall ESCC and GCA patients were not significantly different from that in healthy controls (P>0.05). When stratified by smoking status and family history of UGIC, XRCC2 G4234C SNP had no significant influence on the risk of ESCC and GCA.4 The combined effect of XRCC2 C41657T and G4234C SNPs on ESCC and GCA was analyzed by EH and 2LD software. Compared with the 41657C/4234G haplotype, individuals with the 41657T/4234G haplotype had higher risk in developing GCA (OR=1.40, 95%CI=1.06~1.85). Furthermore, the two SNPs were in linkage disequilibrium (D'=0.864659,χ2=237.94,P=0.00). The XRCC2 C41657T C allele and G4234C G allele were in linkage disequilibrium.5 The distribution of XRCC5 SNPs genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (all P values are above 0.05). The allelotype and genotype distributions of the XRCC5 C74468A SNP in the overall ESCC and GCA patients were not significantly different from that in healthy controls (P>0.05). When stratified by smoking status, XRCC5 C74468A SNP had no significant influence on the risk of ESCC and GCA. When stratified by family history of UGIC, Compared with the C/C genotype, individuals with the A allele (A/C+A/A genotype) in the group with family history of UGIC had higher risk in developing ESCC and GCA (age, gender, smoking status adjusted OR=0.58 and 0.61, 95%CI=0.38~0.90 and 0.38~0.98, respectively).6 The allelotype and genotype distributions of the XRCC5 G74582A SNP in the overall ESCC and GCA patients were not significantly different from that in healthy controls (P>0.05). When stratified by smoking status, XRCC5 G74582A SNP had no significant influence on the risk of ESCC and GCA. When stratified by family history of UGIC, Compared with the A/A genotype, individuals with the G allele (A/G+G/G genotype) in the group with family history of UGIC had higher risk in developing GCA (age, gender, smoking status adjusted OR=0.60, 95%CI=0.38~0.94).7 The combined effect of XRCC5 C74468A and G74582A SNPs on ESCC and GCA was analyzed by EH and 2LD software. It was shown that the two SNPs were in linkage disequilibrium (D'=0.522111,χ2=200.18,P=0.00). Thus, the XRCC5 C74468A C allele and the G74582A A allele were in linkage disequilibrium. The combined analysis of the two XRCC5 SNPs indicated that the C/A haplotype was the most frequent haplotype in the population, which was 51.7%. The haplotype distribution in ESCC and GCA patients was not clearly different from that in healthy controls (P>0.05). Conclusions1 Family history of UGIC increases the risk of developing ESCC and GCA.2 The XRCC2 C41657T polymorphism may be associated with ESCC and GCA development.2.1 The T/T genotype of XRCC2 C41657T SNP significantly increased the risk to developing ESCC, especially in individuals in smoker group. The T/T genotype significantly increased the risk to developing ESCC and GCA in the group without family history of UGIC.2.2 The T allele (C/T+T/T genotype) of XRCC2 C41657T SNP significantly increased the risk to developing GCA, especially in individuals in non-smoker group.3 The XRCC2 G4234C polymorphism alone may not be associated with ESCC and GCA development.4 The XRCC2 C41657T and G4234C SNPs were in linkage disequilibrium. The C41657T C allele tends to be linked to the G4234C G allele. The distribution of the four haplotypes in GCA patients was significantly different from that in healthy control. The 41657C/4234G haplotype was the most frequent haplotype in the population, which was 71.8%. Compared with C/G haplotype, the T/G haplotype significantly increased the risk of developing GCA.5 The A allele(A/C+A/Agenotype) of XRCC5 C74468A SNP may be a protective factor. Individuals with A allele (A/C+A/A genotype) had significantly lower risk to develop ESCC and GCA in the group with family history of UGIC.6 The G allele(A/G+G/Ggenotype) of XRCC5 C74582A SNP may be a protective factor too. Individuals with G allele (A/G+G/G genotype) had significantly lower risk to develop GCA in the group with family history of UGIC.7 The XRCC5 C74468A and G74582A SNPs were in linkage disequilibrium. The C74468A C allele tends to be linked to the G74582A A allele. The 74468C/74582A haplotype was the most frequent in the population, which was 51.7%. The haplotype distribution in ESCC and GCA patients was significantly different from that in healthy control.