Study Of Chemo-sensitivity Associated Biomarkers In Ovarian Cancer

ObjectiveTo explore the biomarkers associated with the chemo-sensitivity in epithelial ovarian cancer, and the correlation between the biomarkers and clinical prognosis of ovarian cancer.Methods1.By reviewing reports on biomarkers of chemoresistance in ovarian cancer, twenty potential factors were chosen for our study, which involved in drug metabolism/transportation mechanism (MDR1, CTR1, HIF-1α, MRP, PXR), DNA damage repair mechanism (PARP1, ERCC1, BRCA1, BRCA2), and cell survival/apoptosis mechanism (AKT1, EZH2, EGFR, VEGF, BCL-2, HDAC1, SURVIVIN, TNF-a, HSP27, RGS17, RASSF1A).2.Forty-two epithelial ovarian cancer spicemens and five normal ovarian tissues were obtained from the tumor bank of our department. All patients hadn’t undergone chemotherapy or radiotherpay before surgery and received TC chemotherapy (taxane combined with carboplatin, i.v.) after surgery. They were classified into chemo-resistant group and chemo-sensitive group according to their responses. The expression of the biomarkers in ovarian cancer tissues was detected by tissue microarray and immunohistochemistry.3. Purified cancer tissues obtained by microdissection were used in qRT-PCR to detect the mRNA expression of the biomarkers.Results1. According to the results of immunohistochemistry, the expression of fourteen factors (MDR1, AKT1, EZH2, PARP1, CTR1, HIF1α, HDAC1, EGFR, VEGF, HSP27, ERCC1, BRCA1, BRCA2and PXR) in the chemo-resistant group were significantly different from that in the chemo-sensitive group, i.e. CTR1was lowly expressed, while the others were highly expressed in chemo-resistant tumors when compared to chemo-sensitive ones.2. According to the ROC analysis of chemo-sensitivity prediction, the AUC (area under curve) of these fourteen factors all proceeded0.7. Meanwhile, the AUC of PARP1and HDAC1was0.904and0.894, respectively.3. Results of survival analysis showed that high expression of MDR1, EZH2, PARP1, HDAC1and EGFR were associated with poorer progression-free survival (PFS). And the high expression of HDAC1and BRCA1were associated with poorer overall survival (OS).4. The multi-variant Cox regression analysis indicated that EZH2, PARP1, HDAC1and EGFR were independent risk factors for PFS, while HDAC1and BRCA1were independent risk factors for OS.5. According to the results of qRT-PCR, the mRNA expression of MDR1, EZH2, PARP1and HDAC1were higher in the chemo-resistant group compared to the chemo-sensitive group. And their AUC in ROC ananlysis of chemosensitivity all proceeded0.7, while the highest reached0.932(HDAC1).6.Survival analysis showed that the mRNA expression of MDR1, EZH2, PARP1, HDAC1and EGFR were also associated with PFS, which were identified as independent risk factors for PFS by multi-variant Cox regression analysis.Conclusions PARP1and HDAC1are promising predictors for the chemo-sensitivity in ovarian cancer. In addition, MDR1, EZH2, PARP1, HDAC1and EGFR are independent risk factors for PFS, while HDAC1and BRCAl are independent risk factors for OS.