ABSTRACT
Cytogenetic, molecular genetic, and functional analyses have implicated chromosome 17 genes in epithelial ovarian cancer (EOC). To further characterize the contribution of chromosome 17 genes in EOC, the Affymetrix U133A GeneChip was used to perform transcriptome analyses of 15 primary cultures of normal ovarian surface epithelial (NOSE) cells and 17 malignant ovarian tumor (TOV) samples of the serous histopathologic subtype. A two-way comparative analysis of 776 known genes and expressed sequences identified 253 genes that exhibited at least a threefold difference in expression in at least one TOV sample compared to the mean of NOSE samples. Within this data set, 99 of the 253 (39.1%) genes exhibited similar patterns of expression across all tested samples, suggesting a high degree of concordance in the chromosome 17 transcriptome. This observation was supported by hierarchical clustering analysis that segregated the TOV and NOSE samples into two separate groups. There were 77 genes that were differentially expressed in at least 50% of the TOV samples. Five genes (AdoRA(2B)at 17p12, CCL2 at 17q12, ACLY at 17q21.2, WIPI1 at 17q24.2, and SLC16A3 at 17q25.3) were significantly (P < 5.13E-11) differentially expressed at least threefold in all serous TOV samples, and all five genes were underexpressed in these TOV samples as compared to the NOSE samples. Interestingly, several of these differentially expressed genes have been previously associated with response to hypoxia.
Subject(s)
Chromosomes, Human, Pair 17/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/genetics , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Adult , Aged , Female , Humans , Middle Aged , RNA, Messenger/genetics , Tumor Cells, CulturedABSTRACT
To address the cellular basis for the response to ovarian cancer treatment, we characterized the chemosensitivity and radiosensitivity of four human epithelial ovarian cancer cell lines that harbor different genetic alterations. The TOV-21G, TOV-81D, OV-90, and TOV-112D cell lines were derived from ovarian tumors (TOV) or ascites (OV) from chemotherapy- and radiotherapy-naive patients and were characterized by their mutation spectrum of BRCA2, TGFbeta-RII, KRAS2, TP53, and CDKN2A. Cells were monitored for survival following exposure at various concentrations to different cytotoxic agents including cisplatin, camptothecin or paclitaxel or to different doses of gamma-irradiation. At the lowest doses, the TGFbeta-RII-mutated and KRAS2-mutated cell line, TOV-21G, and the BRCA2-mutated cell line, TOV-81D, demonstrated a significantly higher sensitivity to cisplatin and gamma-irradiation than the TP53-mutated cell lines, TOV-112D and OV-90. At higher doses, differences between the TP53-mutated lines were observed with TOV-112D being less sensitive to cisplatin than OV-90 that also harbors a CDNK2A mutation. All cell lines were similarly sensitive to high doses of gamma-irradiation. In contrast, sensitivity to camptothecin or paclitaxel was not significantly different between all cell lines, irrespective of the mutation status of BRCA1, BRCA2, TGFbeta-RII, KRAS2, TP53, and CDKN2A. The observed responses to treatment are consistent with the current knowledge concerning BRCA2, TGFbeta-RII, KRAS2, TP53, and/or CDKN2A aberrant function.
