A microRNA survival signature (MiSS) for advanced ovarian cancer.

ABSTRACT

OBJECTIVES: MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression primarily through post-transcriptional modification. We tested the hypothesis that miRNA expression is associated with overall survival in advanced ovarian cancer. METHODS: Cases included newly diagnosed patients with stage III or IV serous ovarian cancer. RNA from a training set of 62 cases was hybridized to an miRNA microarray containing 470 mature human transcripts. Cox Regression was performed to identify miRNAs associated with overall survival. External validation was performed using quantitative RT-PCR miRNA assays in an independent test set of 123 samples. MiRNA targets and associated biologic pathways were predicted in silico. RESULTS: Of all patients, 80% had high-grade, stage IIIC tumors and 64% underwent optimal cytoreduction. The median survival for the entire cohort was 49±4 months. The training set identified 3 miRNAs associated with survival--miR-337, miR-410, and miR-645. An miRNA signature containing miR-410 and miR-645 was most strongly associated with overall survival in the training set (HR=2.96, 95% CI 1.51-5.78). This miRNA survival signature (MiSS) was validated in the test set (HR=1.71, 95% CI 1.05-2.78). The MiSS was independent of FIGO stage and surgical debulking. CONCLUSIONS: The data suggest that an MiSS that contains miR-410 and miR-645 is negatively associated with overall survival in advanced serous ovarian cancer. This signature, when further validated, may be useful in individualizing care for the ovarian cancer patient. Pathway analyses identify biologically plausible mechanisms.