Genotype And Expreesion Of Excision Repair Cross Complementation Group 1 May Influence Outcome To Platinum-based Chemotherapy And Survival In Epithelial Ovarian Cancer Patients

Purpose: Ovarian cancer is one of the three most common gynecological malignancy and the first leading cause of cancer-related death among women; The etiology and pathogenesis remain unclear.Because early-stage malignancy is frequently asymptomatic and difficult to detect and so,by the time of diagnosis, most women have advanced disease,thus the overall 5-year survival rate for ovarian cancer patients is no more than 30%. While epithelial ovarian cancer(EOC) occupies 85% ~ 90% and is the most common type. Currently cytoreductive surgery with platinum-based chemotherapy remains the first-line treatment at first presentation. However,the resistance to the platinum-based chemotherapy becomes the obstacle for the ovarian cancer patient during the treatment.Anti-tumor effect of platinum compounds(carboplatin and cisplatin) is through the combination of cross-linking chain in and between DNA and Pt- DNA adduct. DNA adducts change DNA structure, and then affect DNA replication and inhibit DNA synthesis.DNA repair mechanisms are of great importance to maintain the genetic stability and integrity, and may have an influence on the platinum-basedsensitivity in EOC. Nucleotide excision repair(NER) plays an important role in the DNA repair pathways. While ERCC1(Excision Repair Cross-Complementation Group 1,ERCC1) may be the leading gene in NER,ERCC1–XPF(xerodermapigmentosumgroup F,XPF) heterodimers,the only DNA repair proteins essential for both the NER and DNA interstrand crosslink repair(ICL-R) pathways,are responsible for the 5′incision and cleavage of damaged DNA during the repair process. Not surprisingly, ERCC1 plays a vital role in the recognition and repair of the DNA damage in NER system. Thus, the relationship between ERCC1 gene and sensitivity of platinum-based chemotherapy in ovarian cancer patients becomes the current investigative focus.This study is designed to investigate the relationship between the ERCC1 protein expression and gene polymorphism with drug sensitivity and prognosis in EOC patients.Methods: This study analyzed 172 tumor samples from women who underwent surgery for primary epithelial ovarian cancer between 2008 and 2010 in the Department of Gynecology at the Fourth Hospital of He Bei Medical University, which were confirmed pathologically,. Formalin-fixed, paraffin-embedded(FFPE) tissues were collected from the department of Pathology. DNA was extracted from FFPE samples. Snapshot was used to test the polymorphism status.Immunohistochemistry was used to measure protein expression of ERCC1. All data were evaluated with SPSS statistic 13.0 Software. The χ2 test was used to analyse the relationship between clinical characteristics,expression,methylation with recurrence and death. Logistic regression was used to calculate the OR(odds ratio,OR) and 95%CI(confidence interval,CI);Kaplan–Meier method and adjusted Cox regression modeling were used to examine associations between ERCC1 polymorphism and protein expression with progression-free survival(PFS) and overall survival(OS). All tests performed were two-sided and P-value <0.05 was considered statistically significant.Rusults:1 Statistic analysis showed that:there is a significant difference between prognosis and age,stage and type(P<0.05).2 The analysis of ERCC1 genotype polymorphism and platinum sensitivity of EOC patients: Of 172 EOC patients,the response is 133; the no-response is 39.The genotype frequency in the response and the non-response is respectively83.5%,69.9%(CC) and 16.5%, 30.1%(CT + T T).Compared with CC genotype, patients of CT+TT seem to be more resistant to platinum-based chemotherapy(OR=2.18,95%CI=1.05-4.55).3 The analysis of ERCC1 genotype polymorphism and prognosis of EOC patients : Of 172 EOC patients,the recurrence 91 cases,the unrecurrence 81cases;the death 56 cases,the survival 116 cases. The ERCC1 rs11615 genotype frequency in the recurrence and the unrecurrence is respectively 43.3%,64.4%(CC) and 56.7%,35.6%(CT+TT)(P=0.03). The ERCC1 rs11615 genotype frequency in the death and the survival is respectively 24.7%,41.1%(CC)and 75.3%、58.9%(CT+TT)(P=0.02). Kaplan-Meier survival analysis showed that CT/TT genotype was associated with PFS( P=0.01) and OS( P=0.03) in EOC patients. COX regression also demonstratedthat a shorter PFS(HR=1.65,95%CI=1.07-2.55)and shorter OS( HR=1.93,95%CI=1.11-3.35) were observed in patients with CT+TT genotype.4 There is no significant difference between ERCC1 protein expession and clinicopathologicalfeatures(age、stage、type and grade).5 The analysis of ERCC1 protein expreesion and platinum sensitivity of EOC patients: The frequency in the response and the nonresponse is respectively71.8%、28.2%、81.2%、18.8%. no significant difference was found between ERCC1 protein expression and the sensitivity of platinum-based chemotherapy(P=0.15).6 The analysis of ERCC1 protein expreesion and prognosis of EOC patients: In the 172 epithelial ovarian cancers, we found that ERCC1 protein expreesion was not related with the prognosis. When we stratified analysis with the stage(136 cases of advanced stage), we found that ERCC1 protein expreesionwas significantly associated with respond of epithelial ovarian cancer patients with platinum-based chemotherapy in advanced EOC patients There was significant difference of ERCC1 protein expreesion between the responder and no responder(p=0.03). the higher ERCC1 protein expression may significantly decreased the risk of developing to platinum-resistance(OR=0.42;95%CI=0.19-0.92). those with lower protein expression have a higher recurrence and mortality rate.7 The analysis of ERCC1 protein expreesion and ERCC1rs11615C/T polymorphism of EOC patients:Nonparametric tests showed that there was no significant difference between ERCC1 rs11615C/T polymorphism and protein expreesion(P>0.05).Conclusions:1 ERCC1 rs11615C/T genotype polymorphism may influence the sensitivity of platinum-based chemotherapy and prognosis of EOC patients:patients with T alle gene seem to be more resistant to platinum-based chemotherapy and have a shorter PFS and shorter OS.2 ERCC1 protein expression may have an influence in the respond of platinum-based chemotherapy and prognosis of advanced EOC patients :those with lower protein expression have a higher recurrence and mortality rate the higher ERCC1 protein expression may significantly decreased the risk of developing to platinum-resistance.Those with higher ERCC1 protein expression have a longer PFS and OS.3 ERCC1 rs11615C/T polymorphism may have no influence in protein expression.