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Background: High-grade serous ovarian carcinoma (HG-SOC) is the dominant tumor histologic type in epithelial ovarian cancers, exhibiting highly aberrant microRNA expression profiles and diverse pathways that collectively determine the disease aggressiveness and clinical outcomes. However, the functional relationships between microRNAs, the common pathways controlled by the microRNAs and their prognostic and therapeutic significance remain poorly understood. Methods: We investigated the gene expression patterns of microRNAs in the tumors of 582 HG-SOC patients to identify prognosis signatures and pathways controlled by tumor miRNAs. We developed a variable selection and prognostic method, which performs a robust selection of small-sized subsets of the predictive features (e.g., expressed microRNAs) that collectively serves as the biomarkers of cancer risk and progression stratification system, interconnecting these features with common cancer-related pathways. Results: Across different cohorts, our meta-analysis revealed two robust and unbiased miRNA-based prognostic classifiers. Each classifier reproducibly discriminates HG-SOC patients into high-confidence low-, intermediateor high-prognostic risk subgroups with essentially different 5-year overall survival rates of 51.6-85%, 20-38.1%, and 0-10%, respectively. Significant correlations of the risk subgroup's stratification with chemotherapy treatment response were observed. We predicted specific target genes involved in nine cancer-related and two oocyte maturation pathways (neurotrophin and progesterone-mediated oocyte maturation), where each gene can be controlled by more than one miRNA species of the distinct miRNA HG-SOC prognostic classifiers. Conclusions: We identified robust and reproducible miRNA-based prognostic subsets of the of HG-SOC classifiers. The miRNAs of these classifiers could control nine oncogenic and two developmental pathways, highlighting common underlying pathologic mechanisms and perspective targets for the further development of a personalized prognosis assay(s) and the development of miRNA-interconnected pathway-centric and multi-agent therapeutic intervention. [ABSTRACT FROM AUTHOR]

Objective To validate our earlier observation that 11 chemoresistance-associated mRNAs are molecular markers of poor overall survival in ovarian serous carcinoma. Methods Ovarian serous carcinomas (n = 112) and solid metastases (n = 63; total = 175) were analyzed for mRNA expression of APC , BAG3 , EGFR , S100A10 , ITGAE , MAPK3 , TAP1 , BNIP3 , MMP9 , FASLG and GPX3 using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters and survival. Tumor heterogeneity was assessed in 20 cases with > 1 specimen per patient. APC, BAG3, S100A10 and ERK1 protein expression by immunohistochemistry was analyzed in 58 specimens (38 primary carcinomas, 20 metastases). Results BAG3 (p = 0.013), TAP1 (p = 0.014), BNIP3 (p < 0.001) and MMP9 (p = 0.036) were overexpressed in primary tumors, whereas S100A10 (p = 0.027) and FASLG (p = 0.006) were overexpressed in metastases. Analysis of patient-matched primary carcinomas and metastases showed overexpression of APC (p = 0.022), MAPK3 (p = 0.002) and BNIP3 (p = 0.004) in the former. In primary carcinomas, higher APC (p = 0.003) and MAPK3 (p = 0.005) levels were related to less favorable chemoresponse. Higher S100A10 (p = 0.029) and MAPK3 (p = 0.041) levels were related to primary chemoresistance. Higher BAG3 (p = 0.026) and APC (p = 0.046) levels in primary carcinomas were significantly related to poor overall survival in univariate, though not in multivariate survival analysis. S100A10 protein expression was related to poor chemoresponse (p = 0.002) and shorter overall (p = 0.005) and progression-free (p < 0.001) survival, the latter finding retained in multivariate analysis (p = 0.035). Conclusions Our data provide evidence of heterogeneity in ovarian serous carcinoma and identify APC, MAPK3, BAG3 and S100A10 as potential biomarkers of poor chemotherapy response and/or poor outcome in this cancer. [ABSTRACT FROM AUTHOR]