The Correlation Of DNA Repair Gene XPD Polymorphisms To Ovarian Cancer

Objective: Ovarian cancer is frequent in gynecological tumour, more than 90% comes from epithelial tissue. Without systematical diagnosis method in the early and effective therapy treatment in the late so far, ovarian cancer become the main disease to threaten women's health and life. Though the etopathogenisis of ovarian cancer is not very clear now, genetic and environmental factor play an important role. 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. Nucleotide excision repair is an important pathway to repair DNA damage, which 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 deficiency may be associated with increased tumor susceptibility. Thus, the polymorphism of DNA repair gene may be one of susceptibility factors for ovarian cancer.This study was designed to investigate the correlation of XPD Asp312Asn in exon 10 and Lys751Gln in exon 23 SNPs to the susceptibility of ovarian cancer in north Chinese Han women. By this way, we hope to offer some evidences for the prevention and therapy of ovarian cancer at molecularbiological leval.Methods: 235 ovarian cancer patients and 246 healthy control were recruited as subjects. 235 patients with ovarian cancer were recruited from the gynecology and obstetrics department of the Fourth Affiliated Hospital of Hebei Medical University from December 2001 to November 2006. All the epithelial ovarian cancer patients were histologically confirmed. Ovarian cancer staging was performed by FIGO clinical standard. 246 healthy volunteers who had no clinical evidence of ovarian cancer or any other malignant tumours were randomly selected from Chinese blood donors as control subjects. All cases and controls were from Chinese Han population.The informed consent was got from all the recruited subjects. Five ml of venous blood from each subject was drawn in vacutainer tubes. The genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. Polymorphism of XPD gene was analyzed by PCR-restriction fragment length polymorphism analysis (RFLP).Statistical analyse was performed using the 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 XPD 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 XPD 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.Results:1 The distribution of XPD G/A SNP in exon 10 and A/C SNP in exon 23 genotypes among healthy controls did not significantly deviate from the expected Hardy-Weinberg equilibrium( P >0.05).2 XPD G/A SNP in exon 10: G/G,G/A and A/A genotype frequency in ovarian cancer patients and healthy controls were 80.9%, 19.1%, 0 and 85.0%, 15.0%, 0, respectively. Due to there was no A/A genotype, we combined A/A and G/A genotype,and found no statistical difference between the two groups (P>0.05). Contrast with G/G, G/A genotype can not increase the risk of developing ovarian cancer(OR=0.747,95%CI=0.464~1.205). For XPD Asp312Asn polymorphism, the G and A allele frequencies in ovarian cancer patients and healthy controls were 90.4%, 9.6% and 92.5%, 7.5%, respectively. There was no statistical difference between the two groups (P>0.05).3 For XPD A/C SNP in exon 23, A/A,A/C and C/C genotype frequencies in ovarian cancer patients and healthy controls were 77.9%, 20.9% , 1.2% and 81.3%, 18.3%, 0.4%, respectively. There was no statistical difference between the two groups (P>0.05). Contrast with A/A genotytpe, A/C and C/C can not increase the risk of developing ovarian cancer. The A and C allele frequencies in ovarian cancer patients and healthy controls were 88.3%, 11.7% and 90.4%, 9.6%, respectively. There was no statistical difference in the allele distribution between the cases and controls (P>0.05).4 When the epithelial ovarian cancer patients were grouped according to the pathological characteristics, no significant difference was observed between each of the pathological type and controls for XPD312 and XPD751 genotype. There was no significant difference between each of the pathological type and contrals for XPD312 allelotype either. But from the distribution of XPD751 allelotype, we found slightly different trend between serous cystadenocarcinoma and the controls (χ2=3.629, P=0.057). The Gln allele may be the suspicious dangerous allele in serous cystadenocarcinoma (OR=1.64, 95%CI=0.903~2.979).5 When the epithelial ovarian cancer patients were divided into two groups according to the FIGO standard, there wasn't statistical difference between the earlier group and the advanced group for Asp312Asn. But the Lys751Gln genotype distribution between the earlier stage group and advanced stage group was significantly different. It identified that ovarian cancer patients with Gln allele (Lys/Gln or Gln/Gln) were more likely to take invasion and transferation (OR=2.205, 95%CI=1.038~4.688, P=0.037).6 The combined effect of XPD G/A and A/C SNPs was analyzed by EH and 2LD software .It was shown that the two SNPs were in linkage disequilibrium (D'=0.524386,χ2=104.17, P=0.00). Thus, the XPD G allele in exon 10 was likely to in linkage disequilibrium with A allele in exon 23. The G/A haplotype was the most common haplotype, which was 83.7%. The haplotype distribution in ovarian cancer patients was not clearly different from that in healthy controls (P>0.05).Conclusions:1 The XPD Asp312Asn and Lys751Gln polymorphisms may not play a role in the genetic susceptibility to the development of ovarian cancer. By pathologic type, the A,C allele of XPD Lys751Gln have a slightly different trend between ovarien cancer cases and controls. The C allele may be the suspicious dangerous allelotype of developing ovarian cancer.2 There was significantly difference between the early and late ovarian cancer patients for the genotype of XPD Lys751Gln polymorphism. The A/C and C/C genotype may be used as a stratification marker according to the standards of FIGO for ovarian cancer.3 The XPD G/A SNP in exon 10 and A/C SNP in exon 23 were in linkage disequilibrium. The G allele in exon 10 tends to be linked with the A allele in exon 23. The haplotype distribution had no influence on the risk of ovarian cancer.