| Objective: Ovarian cancer (OC) is one of the most commongynecological malignancies in female reproductive tract, and more than90%are epithelial ovarian cancer (EOC). Due to lack of early symptoms,approximately70%of ovarian cancer presents advanced stage whendiagnosed, so ovarian cancer patients’overall5-year survival is still about30%. Now, platinum-based chemotherapy has become the first line treatmentstrategy for ovarian cancer patients after cytoreductive surgery. In spite ofunceasing optimizing the surgery, the overall5-year survival is not obviouslyimproved. Platinum-resistance has become the principal disability on the EOCpatients’ treatment.The difference of DNA repair capacity may be related to the sensitivityvariance of EOC patients to platinum chemotherapy. Nucleotide excisionrepair (NER) path is considered the main path of DNA-injury repair. Excisionrepair cross-complementing1(ERCC1) is the important gene of NER path.ERCC1protein and Xeroderma pigment group F (XPF) form heterodimer,which develop the recognition function of DNA-injury in the initial stage andrepresent enzymic activity of5′endonuclease at later stage, and then executesa5′incision into the damaged DNA strand. So ERCC1is the key protein ofNER path. Association between ERCC1gene and sensitivity in EOC patientswith platinum is a heat topic. The aim of our study was to explore therelationship between tag single nucleotide polymorphism (tagSNP) of ERCC1and clinical outcomes of EOC patients treated with platinum-basedchemotherapy.Methods: We chose6tagSNPs (rs11615, rs3212986, rs735482,rs3212955, rs12610134, rs3212958) from ERCC1using the Haploviewsoftware. The six gene polymorphisms genotypes of220EOC patients were determined by Snapshot method. All patients were followed up for three years.Primary clinical outcomes parameter contained EOC patient treatmentresponse to platinum-based chemotherapy (TR), progression-free survival(PFS) and overall survival (OS).Statistical analysis was performed using SPSS ver.13.0software package.The associations between clinical characteristics and outcomes of EOCpatients were performed by means of two-sided contingency tables using theχ2-test. Unconditional logistic regression models were used to calculate oddsratios (OR) and their95%confidence intervals (CI). Survival analyses wereperformed using the Kaplan–Meier analysis with log-rank test. Theassociations of ERCC1gene tagSNPs and the risk of recurrence and deathwere analyzed by the Cox proportional hazard model, with adjustment for age,FIGO stage, pathology, grade, tumor residual size. A probability level of5%was considered significant.Results:1The associations between clinical characteristics and outcomes of EOCpatients. There were obvious relationships between clinical characteristics andclinical outcomes of EOC patients. Clinical factors that included age over50years old, advanced stage, and tumor residual over1cm associated with bothincreased recurrence and decreased survival (P<0.01). Patients with low gradeincreased the risk of recurrence (P=0.04). Patients with histology were notsignificantly associated with the outcome variables in this study (P＞0.05).2The polymorphisms of ERCC1gene and sensitivity to platinum-basedchemotherapy in ovarian cancer patients. A total of147(66.8%) patientsresponded to the platinum-based chemotherapy and73(33.2%) patients didnot. The C/C, C/T, T/T genotypes frequencies of ERCC1rs11615C/T were53.0%,45.6%,1.4%and52.1%,35.6%,12.3%in responders toplatinum-based chemotherapy and non-responders. The genotypesfrequencies of ERCC1rs11615C/T were significantly different between thetwo groups (P＜0.01). Compared with the C/C genotype, the T/T genotypedecreased the response to platinum-based chemotherapy in EOC patients (OR=6.22,95%CI=1.12~34.42). The genotypes frequencies ofERCC1rs3212986, rs735482, rs3212955, rs12610134did not have asignificant difference between the responders to platinum-based chemotherapyand non-responders (P＞0.05).3The polymorphisms of ERCC1gene and clinical outcomes of ovariancancer patients.135(61.4%) of all patients recurred and85(38.6%) patientsdid not. The C/C, C/T, T/T genotype frequencies of ERCC1rs11615C/T were54.8%,37.0%,8.2%and49.4%,50.6%,0.0%in recurrence group andnon-recurrence group. The genotype frequencies of ERCC1rs11615C/T weresignificantly different between the two groups (P＜0.01).92(41.8%) of allpatients were death and128(58.2%) patients were live. The C/C, C/T, T/Tgenotype frequencies of ERCC1rs11615C/T were51.1%,39.1%,9.8%and53.9%,44.5%,1.6%in two groups. The genotype frequencies ofERCC1rs11615C/T were significantly different between the two groups(P=0.02). Survival analysis showed that the three genotypes frequenciesdistribution of ERCC1rs11615C/T was associated with the PFS (P＜0.01) andOS (P＜0.01) of EOC patients. Cox’s multivariate analysis suggested thatpatients with T/T genotype had a shorter PFS (HR=2.19,95%CI=1.14~4.22)and OS (HR=2.22,95%CI=1.06~4.64) compared with those carrying C/Cgenotype (adjusting for age, FIGO stage, pathology, grade and tumor residualsize).The genotypes frequencies distribution of ERCC1rs3212986, rs735482,rs3212955and rs12610134tagSNPs did not have a significant differencebetween the recurrence and non-recurrence group, death and live group. Andcompared with the wild type, the mutant of other tagSNPs may be notassociated with PFS and OS of EOC patients.Conclusion:1There was significantly association between ERCC1rs11615C/T SNPand response to platinum-based chemotherapy or outcomes. Patients with T/Tgenotype decreased the response to platinum-based chemotherapy, and had ashorter PFS and OS compared with those carrying C/C genotype. 2There were no relationships between tagSNPs of ERCC1rs3212986,rs735482, rs3212955, rs12610134and response to platinum-basedchemotherapy or clinical outcomes of epithelial ovarian cancer patients.3ERCC1rs11615SNP may become a valuable prognostic biomarker forEOC patients treated with platinum-based chemotherapy. |
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