Correlation Of DNA Double Strand Break Repair Gene XRCC2 And XRCC5 Polymorphisms To Lung Cancer

Objective: Lung cancer is one of the most common malignant tumor, it account for 17% of the death of malignant tumor. Despite major advances in lung cancer dignosis and treatment in the past decades, the prognosis of patients with lung cancer has improved only minimally. The overall 5-year survival rate remain less than 15%. So precaution and early diagnosis are the key to enhance the survival of lung cancer. Except for the smoking, the effect of susceptibility was focused on the study of lung cancer. The development of molecular biology make it possible that we can detect suscepbility of lung cancer by using these markers. It will be beneficial to the precaution and early diagnosis of lung cancer.DNA double strand break (DSB) repair gene have high incidence of polymorphism. Polymorphism in DNA repair gene may cause the diverse DNA repair capacity and influence an individual′s susceptibility to carcinogenesis. It was shown that DNA-repair function deficiency may be associated with increased cancer risk. DSB repair-gene polymorphisms produce the differences of DNA-repair function,these differences are the key to be associated with increased lung cancer risk. It is important to know whether DSB repair-gene polymorphisms may affect risk of the occurrence and progression of lung cancer.This study was designed to investigate the possible association of functional polymorphisms of XRCC2 C41657T,G4234C and XRCC5 C74468A,G74582A genes with susceptibility of lung cancer in north China.Methods: This hospital-based case-control study included 271 lung patients (107 with squamous cell carcinoma,80 with adenocarcinoma,32 with adenosquamous carcinoma and 52 with small cell lung cancer) and 280 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) or primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR). The genotype and allele distribution were compared.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 lung cancer patients and healthy controls was performed by means of two-sided contingency tables using Chi-square test. The XRCC2 and XRCC5 haplotype frequencies were estimated by using EH linkage software. The odds ratio (OR) and 95% confidence Interval (CI) were calculated using an unconditional logistic regression model and adjusted by age, gender and smoking status accordingly.Results:1 The frequency of smokers in lung cancer patients(65.7%) was significantly higher than that in healthy controls (42.9%) (χ2=28.9, P<0.05). Smoking may increase the risk of developing lung cancer(age and gender adjusted OR=3.47, 95%CI=2.28～5.29).2 The distribution of XRCC2 C41657T SNP genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (P>0.05). Frequency of the T allele in lung cancer patients was 20.8%, which was significantly higher than that in healthy controls (12.9%) (χ2=12.59, P<0.05). The distribution of genotypes (C/C,C/T,T/T) in the overall lung cancer patients also was significantly different from that in healthy controls(χ2=12.20, P<0.05). Compared with C/C genotype, the combination of C/T and T/T of XRCC2 C41657T and C/T genotype both increased the risk of lung cancer (age, gender and smoking status adjusted OR=1.77 and 1.66, 95%CI=1.21~2.60 and 1.12~2.48, respectively). Stratification analysis according to histological type showed that compared with C/C genotype, the combination of C/T and T/T of XRCC2 C41657T and C/T genotype both increased the risk of adenocarcinoma (age, gender and smoking status adjusted OR=2.59 and 2.51, 95%CI=1.51～4.45 and 1.43～4.39, respectively).When stratified by smoking status, compared with the C/C genotype, the combination of C/T and T/T genotype and C/T genotype both increased the risk of lung cancer in non-smokers (age and gender adjusted OR=2.46 and 2.56, 95%CI=1.38～4.38 and 1.41～4.68, respectively).3 The distribution of XRCC2 G4234C SNP genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (P>0.05). The genotype and allele distribution of the XRCC2 G4234C SNP in the patients with lung cancer was not significantly different from that in healthy controls (all P>0.05). Stratification analysis according to histological type showed that Compared with G/G genotype, the combination of G/C and C/C of XRCC2 G4234C increased the risk of small cell lung cancer (age, gender and smoking status adjusted OR=1.92; 95%CI=1.03～3.60).4 The combined effect of XRCC2 C41657T and G4234C SNPs on lung cancer was analyzed by EH software. The four haplotypes distribution of the XRCC2 SNP in the patients with lung cancer was significantly different from that in healthy controls (χ2=12.90, P<0.05). Frequency of the 41657T/4234G haplotype in lung cancer patients was 17.8%, which was significantly higher than that in healthy controls (11.0%) (χ2=10.80, P<0.01). Compared with the 41657C/4234G haplotype, the 41657T/4234G haplotype had higher risk in developing lung cancer (OR=1.79, 95%CI=1.26～2.53). 5 The distribution of XRCC5 SNPs genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (all P>0.05). The allelotype and genotype distributions of the XRCC5 C74468A SNP in the lung cancer patients were not significantly different from that in healthy controls (P>0.05). Stratification analysis according to histological type and smoking status showed that XRCC5 C74468A SNP had no significant influence on the risk of lung cancer.6 The allelotype and genotype distributions of the XRCC5 G74582A SNP in the lung cancer patients were not significantly different from that in healthy controls (P>0.05). When stratified by histological type and smoking status, XRCC5 G74582A SNP had no significant influence on the risk of lung cancer.7 The combined effect of XRCC5 C74468A and G74582A SNPs on lung cancer was analyzed by EH software. It was indicated that the 74468C/74582A haplotype was the most frequent haplotype in the population, which was 52.5%. The four haplotypes distribution in lung cancer patients was not clearly different from that in healthy controls (P>0.05).Conclusions:1 Smoking may increase the risk of developing lung cancer.2 Compared with C/C genotype, People with the combination of C/T and T/T of XRCC2 C41657T and C/T genotype have significantly increased risk for lung cancer, especially for adenocarcinoma. 3 The combination of C/T and T/T genotype and C/T genotype both increased the risk of lung cancer in non-smokers .4 Compared with G/G genotype, the combination of G/C and C/C of XRCC2 G4234C increased the risk of small cell lung cancer.5 The 41657T/4234G haplotype significantly increased the risk of developing lung cancer, compared with 41657C/4234G haplotype.6 The XRCC5 C74468A or G74582A polymorphism was not associated with susceptibility in lung cancer. All the haplotypes of XRCC5 C74468A and G74582A were not associated with risk of the development of lung cancer.