Association Study Of Clinico-pathological Factors And FREM1, GSTT1, ISG20L1, STARD5, 15q25.3 And Paclitaxel/platinum Chemotherapy Response In Epithelial Ovarian Cancer

BACKGROUND AND PURPOSE:Primary and acquired chemoresistance are the main cause of treatment failure in advanced epithelial ovarian cancer. Plenty of studies tried to investigate the relvance between clinico-pathological factors, genes and chemotherapy response to evaluate the potencial predictive value of markers. However, none of the reported alterations in these genes can reliably predict chemotherapy response likely because tumour progress and response to chemotherapy are multifactorial. The difference of chemosensitivity among tumors can not be attributed to the disturbance of a single gene, but rather to the combined influence of many genes. Accordingly, high-throughput molecular techniques might be more useful in the context. Our pilot study applied Array CGH (Array Comparative Genomic Hybridization) to find the genes with different copy-number changes between resistant and sensitive epithelial ovarian cancers after paclitaxel/platinum chemotherapy. As a result, four genes (FREM1, GSTT1, ISG2OL1 and STARD5) and one chromosome fragment (15q25.3) were identified through validation. Aberrations in 15q25.3 detected by FISH (fluorescence in situ hybridization) and relative copy number changes of the above four genes detected by Real-time PCR were both correlated with TTR (time to recurrence). The purpose of this study is to further validate the correlation between the four genes and 15q25.3 and paclitaxel/platinum chemotherapy response using additional large independent ovarian cancer samples. Assciation between clinico-pathological factors and chemotherapy response was also analyzed retrospectively.MATERIALS AND METHODS:One hundred and three tissue specimens from epithelial ovarian cancer patients who underwent primary cytoreductive surgery followed by paclitaxel/platinum chemotherapy were collected in operation room randomly and frozened according to the experimental requirements. All tissues were maded into pathological sections and the proportion of cancer cells of all samples was more than 30% microscopically. A retrospective review of several clinical and pathologic factors which may have correlation to chemotherapy response was conducted. The relative copy numbers of four genes from 103 samples were detected using Real-time PCR. The aberrations of chromosome fragment 15q25.3 from 84 samples were detected by FISH and experimental results of 38 specimens can be analyzed. The expression of STARD5 protein was detected using immunohistochemistry staining in 45 specimens. Statistical analysis including Chi-square test, Kaplan-Meier survival analysis, Log-rank test and Cox proportional hazard model were used to assess the relevance between clinical and pathologic factors, copy number changes of four genes, aberration of 15q25.3, expression of STARD5 protein and the paclitaxel/platinum chemotherapy response.RESULTS:Kaplan-Meier survival analysis in 103 samples showed that FIGO stage, residual tumor, neoadjuvant chemotherapy had significant relevance with TTR(P<0.05). Log-rank test in 53 samples which undergone pelvic lymphadenectomy found that patients with positive pelvic lymph nodes and negative pelvic lymph nodes had significant difference in TTR (31months vs.8months, P=0.001). Multivariate analysis found that residual tumor volume, neoadjuvant chemotherapy were independent factors with TTR(P<0.05). Analysis showed improved TTR for patients with microscopic residual disease compared with patients with 0 to 1.0cm and> 1.0cm residual disease (P <0.05,29months vs.8months and 6months).Whereas, patients with 0 to 1.0 and> 1.0cm residual disease had no significant difference in TTR (P=0.069). Chi-square test revealed that the copy number changes of GSTT1 in 103 specimens were associated with chemotherapy response significantly (P=0.04). Significant correlation was observed between expression of STATRD5 protein and chemotherapy response using Chi-square test (P=0.044). Kaplan-Meier survival analysis and Log-rank test revealed that the copy number changes of STARD5 in 45 specimens which were also detected by IHC were associated with TTR significantly(P=0.011). Patients who had increased copy number of STARD5 were easier to recur in short time than patients with decreased copy number (median TTR,3months vs. 10months). No significant correlation had been found between copy number changes of FREM1, ISG20L1, aberrations in 15q25.3 and response to paclitaxel/platinum chemotherapy.CONCLUSIONS:Residual tumor volume was an independent prognositic factor in epithelial ovarian cancer. Patients with positive pelvic lymph nodes tended to recur earlier than patients with negative lymph nodes. Patients who were administered neoadjuvant chemotherapy in our study had worse prognosis than patients who were not. Acquired chemoresistance induced by neoadjuvant chemotherapy might be one of the reasons. Patients with decreased copy number of GSTT1 or negative expression of STARD5 tended to be chemosensitive for paclitaxel/platinum chemotherapy. Further study was needed to investigate more strong correlation between these four genes, chromosome fragment 15q25.3 and response to paclitaxel/platinum chemotherapy.