Integrative Network Analysis Reveals a MicroRNA-Based Signature for Prognosis Prediction of Epithelial Ovarian Cancer

BACKGROUND: Epithelial ovarian cancer (EOC) is a heterogeneous disease, which has been recently classified into four molecular subtypes, of which the mesenchymal subtype exhibited the worst prognosis. We aimed to identify a microRNA- (miRNA-) based signature by incorporating the molecular modalities involved in the mesenchymal subtype for risk stratification, which would allow the identification of patients who might benefit from more rigorous treatments. METHOD: We characterized the regulatory mechanisms underlying the mesenchymal subtype using network analyses integrating gene and miRNA expression profiles from The Cancer Genome Atlas (TCGA) cohort to identify a miRNA signature for prognosis prediction. RESULTS: We identified four miRNAs as the master regulators of the mesenchymal subtype and developed a risk score model. The 4-miRNA signature significantly predicted overall survival (OS) and progression-free survival (PFS) in discovery (p=0.004 and p=0.04) and two independent public datasets (GSE73582: OS, HR: 2.26 (1.26-4.05), p=0.005, PFS, HR: 2.03 (1.34-3.09), p<0.001; GSE25204: OS, HR: 3.07 (1.73-5.46), p<0.001, PFS, HR: 2.59 (1.72-3.88), p<0.001). Moreover, in multivariate analyses, the miRNA signature maintained as an independent prognostic predictor and achieved superior efficiency compared to the currently used clinical factors. CONCLUSIONS: In conclusion, our network analysis identified a 4-miRNA signature which has prognostic value superior to currently reported clinical covariates. This signature warrants further testing and validation for use in clinical practice.