Association Of Single Nucleotide Polymorphism In DNA Repair Gene With The Clinical Outcome To Platinum-based Chemotherapyin Epithelial Ovarian Cancer

Objective: Platinum agents are known to act through the formation ofinterstrand and intrastrand DNA cross-links, changing the DNA conformationthat may affect the replication and inhibit the synthesis of the DNA. One ofthe mechanisms by which the tumor cells develop resistance to platinumagents is the enhanced repair of the bulky DNA adducts. However,inefficient DNA repair genotypes result in decreased removal of platinumadducts and improved clinical response. Therefore, DNA repair capacity isclearly an important determinant of the resistance to platinum agents. In thisstudy, we investigated the association between polymorphisms of XPC, XPD,XRCC1genes and clinical outcome of epithelial ovarian cancer (EOC)patients treated with platinum-based chemotherapy.Methods: The study included213patients who had presented fortreatment of ovarian neoplasms to the forth affiliated hospital of Hebeimedical university between December2002and June2008. Eligibilitycriteria for this cohort included newly diagnosed, histologically confirmedprimary epithelial ovarian cancer in women of any age and Han nationality.The patients were excluded from this study if they had neoadjuvantchemotherapy and radiotherapy before surgical staging. Blood samples wereobtained after informed consent of the participants prior to their inclusion inthe study. All patients had been evaluated according to the FIGO surgicalstaging system.Eight SNPs (XPC Ala499Val, Lys939Gln, PAT+/-, XPD Asp312Asn,Lys751Gln and XRCC1Arg194Trp、Arg280His、Arg399Gln) were assessedin213patients with epithelial ovarian cancer using a polymerase chainreaction-restriction fragment-length polymorphism (PCR-RFLP) and primer introduced restriction analysis-polymerase chain reaction (PIRA-PCR)technique.The distributions of the variables by outcomes of interest among patientswere compared using the χ2test. To adjust for age, stage, grade, tumorresidual, and histology status, unconditional logistic regression analysis wasperformed. ORs and95%CIs were calculated as an estimate of relative risk.Kaplan-Meier curves were constructed in order to investigate survivaldifference between the wild-type and variant genotypes. The wild-type allelesas reference, differences were tested for statistical significance using thelog-rank test. HRs and95%CIs were calculated using multivariate Coxproportional hazard models to adjust for appropriate variables, such as age,stage, grade, tumor residual, and histology status. The SPSS software(version.13.0, SPSS Inc., Chicago, IL,USA) was used for all analyses, allstatistical tests were two-sided, and P-values <0.05were consideredstatistically significant.Results:1No significant differences in genotype and allelotype distributions ofeight SNPs (XRCC1Arg194Trp, Arg280His, Arg399Gln and XPDAsp312Asn, Lys751Gln) were found between responders and not respondersof all patients.2The median progression-free survival (PFS) of patients carryingLys/Lys and Lys/Gln+Gln/Gln genotype of XPC Lys939Gln polymorphismwere25and12months, respectively. Kaplan-Meier estimates demonstratedthat statistical significant difference was found between the genotypes andPFS of EOC cases (P=0.039). Cox’s multivariate analysis suggested thatthere are no associations between genotype of Lys/Lys genotype and PFS ofepithelial ovarian cancer to platinum-based chemotherapy compared withthose carrying the Lys/Gln+Gln/Gln genotype (P>0.05).3There are no associations between the XPC (Ala499Val, PAT+/-), XPD(Asp312Asn, Lys751Gln), XRCC1(Arg194Trp, Arg280His and Arg399Gln)polymorphisms and patients recurrence with epithelial ovarian cancer when treated by platinum-based chemotherapy.4The median overall survival (OS) of patients carrying Lys/Lys andLys/Gln+Gln/Gln genotype of XPC Lys939Gln polymorphism were31.1and27.8, respectively. Kaplan-Meier estimates demonstrated that statisticalsignificant difference was found between the genotypes and PFS of EOC cases(P=0.048). Cox’s multivariate analysis suggested that the patients ofepithelial ovarian cancer with the Gln allele had an increased risk of death(HR=1.75;95%CI=1.06-2.91) compared with those with the Lys/Lysgenotype.5There are no associations between the XPC (Ala499Val, PAT+/-), XPD(Asp312Asn, Lys751Gln), XRCC1(Arg194Trp, Arg280His and Arg399Gln)polymorphisms and patients survival with epithelial ovarian cancer whentreated by platinum-based chemotherapy.Conclusion:1No significant differences in genotype and allelotype distributions ofeight SNPs (XRCC1Arg194Trp, Arg280His, Arg399Gln; XPD Asp312Asn,Lys751Gln and XRCC1Arg194Trp, Arg280His, Arg399Gln) were foundbetween responders and not responders of all patients.2There are no associations between the XPC Ala499Val, Lys939Gln,PAT+/-; XPD Asp312Asn, Lys751Gln and XRCC1Arg194Trp, Arg280His,Arg399Gln polymorphisms and patients recurrence with epithelial ovariancancer when treated by platinum-based chemotherapy.3The results indicated that the XPC Lys939Gln polymorphism maycorrelate with clinical outcome of patients with epithelial ovarian cancer whentreated by platinum-based chemotherapy in Northern China.4There are no associations between the XPC Ala499Val, PAT+/-; XPDAsp312Asn, Lys751Gln and XRCC1Arg194Trp, Arg280His, Arg399Glnpolymorphisms and OS of epithelial ovarian cancer patients when treated byplatinum-based chemotherapy.