The Associated Between The Polymorphisms Of XPG Gene And The Clinical Outcome Of Epithelial Ovarian Cancer Patients With Platinum-based Chemotherapy

Objective: Ovarian cancer is the most common cause of death among thegynecologic malignancies in China. Epithelial ovarian cancer (EOC) occupies90%of all malignant ovarian tumors in women. Lack of effective screeningstrategies and the absence of symptoms in early-stage of disease, result inmost of patients were at an advanced stage in their first diagnostic. Theplatinum-based chemotherapy is the first-line chemotherapy followingcytoreductive surgery for advanced EOC. However, approximately30%ofpatients failed to respond to treatment, and up to80%of patients in initialresponders eventually relapsed. Platinum-resistant is the most common causeof decrease progression-free survival (PFS) and overall survival (OS) and theoverall5-year survival rate is25%-30%. Therefore, identification of patientswho are platinum resistant before therapy could lead to better selection oftherapy and could improve survival. It is very important to find the molecularmarkers for predicting the ovarian carcinoma patients sensitive to platinumchemotherapy, which will facilitate to achieve individualized therapy andeffectively improve5-year survival rate for ovarian cancer patients.Platinum-based chemotherapy exerts its toxic effects by covalentlybinding cellular DNA forming platinum-adducts within the DNA, and theability of tumor cells to repair chemotherapy induced damage maysignificantly impact tumor response to platinum-based agents. Nucleotideexcision repair (NER) is a complex DNA repair mechanism that is responsiblefor the removal of a large of DNA lesion including platinum-inducedinterstrand crosslinks. XPG play an important role in the NER, besides canexecutes a3’ incision into the damage DNA strand, forms a heterodimer withxeroderma pigmentum F and executes a5’ incision into the damage DNA strand.Methods: The case retrospective study239epithelial ovarian cancerpatients. All patients were diagnosed by pathology after operation. Venousblood (5mL) from each subject was collected into Vacutainer tubes containingethylenediamine tetraacetic acid and stored at4°C. Genomic DNA wasextracted by using proteinase K digestion followed by a salting out produce.The nine tagSNPs (XPG rs1047768, rs2227869, rs4150387, rs17655,rs2296147, rs3759500, rs4150360and rs4150383) were genotyped by allelicspecific multiple ligase detection reactions (LDR) method.We searched the single nucleotide polymorphisms (SNPs) information ofXPG gene in NCBI dbSNP and Ensembl database and found that there were466SNPs in XPG gene. We selected the tagSNPs of XPG gene in ChineseHan population inquired in Hapmap database, and possessing the minor allelefrequency (MAF)>10%.Statistical analysis was performed using the SPSS13.0software package(SPSS Company, Chicago, IL, USA). Fisher’s exact test was used tocompare the genotypes and clinical pathological variables. The odds ratio(OR) and95%confidence interval (CI) were calculated using logisticregression. Survival analyses were performed using the Kaplan–Meieranalysis with log-rank test. The association of each SNP with the risk ofrecurrence and death was analyzed by the Cox proportional hazard modeladjusting of age, histology and stage. A p-value below5%was considered assignificant.Results:1We indentified nine tag SNPs (rs1047768, rs2227869, rs4150387,rs17655, rs2296147, rs3759500, rs4150360, rs4150383and rs751402) of theXPG gene. No genetic variation was observed at rs41503872The association between clinical characteristics and clinical outcome ofovarian cancer patientsIn the239epithelial ovarian cancer the clinical factors including thediagnosed age, stage and the tumor residual size were significantly associated with clinical outcome of ovarian cancer patients, i.e. the diagnosedage older than50year, advanced stage and tumor residual size over1cm maysignificantly increase recurrence and decrease survival of epithelial ovariancancer patients.3The nine tagSNPs of XPG gene and response to platinum-basedchemotherapy in ovarian cancer patientsIn the239epithelial ovarian cancers, we found that XPG tagSNPs werenot related with the chemotherapy response. When we stratified analysis withthe age, we found that the genotype frequencies of XPG rs1047768C/Tpolymorphism was significantly associated with respond of epithelial ovariancancer patients with platinum-based chemotherapy in subjects that were olderthan50year. There was significant difference of allele frequency between theresponder and no responder (P=0.039), the frequency (TT and CT/CC) was47.7%、52.3%and61.5%、38.5%, respectively. Compared with the TTgenotype, the C allele (CT/CC genotype) may significantly decreased the riskof developing to platinum-resistance (OR=0.49,95%CI=0.24~0.98). Theother gene polymorphisms are not associated with respond of epithelialovarian cancer patients with platinum-based chemotherapy.4The tagSNPs of XPG gene and clinical outcome of ovarian cancerpatientsIn the239epithelial ovarian cancers, we found that the XPG tagSNPswere not related with the clinical prognosis. In the subjects that were olderthan50year, we found that rs1047768C/T and rs2296147C/T polymorphismswere associated with the clinical outcomes. The mean progression-freesurvival (PFS) of patients carrying TT genotype and C allele of XPGrs1047768C/T were19.69and23.66months, and the mean overall survival(OS) were26.81and28.48months, respectively. Mean PFS of patientscarrying TT genotype and C allele of XPG rs2296147C/T were20.46and23.33months, and the mean OS were27.10and29.70months, respectively.Survival analysis showed that the XPG rs1047768C/T and rs2296147C/Tpolymorphisms were associated with survival prognosis of EOC patients. Cox’s multivariate analysis suggested that EOC patients, compared with thosecarrying the rs1047768TT genotype, carry with the rs1047768C allele mayhave a lower risk of disease progression (HR=0.57;95%CI=0.38-0.87) anddeath (HR=0.56;95%CI=0.34-0.94). The rs2296147C allele may lower therisk of disease progression and death (PFS, HR=0.63,95%CI=0.41~0.98；OS,HR=0.50;95%CI=0.28-0.87) in ovarian cancer.Conclusions:1The XPG tagSNPs were not related with the epithelial ovarian cancerclinical outcomes.2For ovarian cancer patients that were older than50year, the XPGrs1047768C/T polymorphism may play as the markers in predict the clinicaloutcomes of ovarian cancer. The rs1047768C allele may associated withreduce the risk of developing platinum-resistance, disease progression anddeath. The rs2296147C allele may associated with reduce the risk ofdeveloping platinum-resistance and death.3The rs2296147C/T polymorphism was associated with reduce the riskof disease progression and death in EOC.