Transcription factor-microRNA-target gene networks associated with ovarian cancer survival and recurrence

Abstract

The identification of reliable transcriptome biomarkers requires the simultaneous consideration of regulatory and target elements including microRNAs (miRNAs), transcription factors (TFs), and target genes. A novel approach that integrates multivariate survival analysis, feature selection, and regulatory network visualization was used to identify reliable biomarkers of ovarian cancer survival and recurrence. Expression profiles of 799 miRNAs, 17,814 TFs and target genes and cohort clinical records on 272 patients diagnosed with ovarian cancer were simultaneously considered and results were validated on an independent group of 146 patients. Three miRNAs (hsa-miR-16, hsa-miR-22*, and ebv-miR-BHRF1-2*) were associated with both ovarian cancer survival and recurrence and 27 miRNAs were associated with either one hazard. Two miRNAs (hsa-miR-521 and hsa-miR-497) were cohort-dependent, while 28 were cohort-independent. This study confirmed 19 miRNAs previously associated with ovarian cancer and identified two miRNAs that have previously been associated with other cancer types. In total, the expression of 838 and 734 target genes and 12 and eight TFs were associated (FDR-adjusted P-value <0.05) with ovarian cancer survival and recurrence, respectively. Functional analysis highlighted the association between cellular and nucleotide metabolic processes and ovarian cancer. The more direct connections and higher centrality of the miRNAs, TFs and target genes in the survival network studied suggest that network-based approaches to prognosticate or predict ovarian cancer survival may be more effective than those for ovarian cancer recurrence. This study demonstrated the feasibility to infer reliable miRNA-TF-target gene networks associated with survival and recurrence of ovarian cancer based on the simultaneous analysis of co-expression profiles and consideration of the clinical characteristics of the patients.

Figure 1. Probability of ovarian cancer survival for patients that have lower grade (I and II) tumors (black lines) or higher (Rest) grade tumors (gray lines) and high (dashed lines) or low (solid line) levels of hsa-miR-521.

Figure 2. Probability of ovarian cancer non-recurrence for patients receiving the treatment chemotherapy only, chemotherapy along with another treatment, or some other treatment or combination of treatments except chemotherapy that have high or low levels of hsa-miR-497.

Figure 3. Network of microRNAs, transcription factors, and target genes associated with survival in ovarian cancer.

(Node Shape: microRNA = diamond, target gene = circle, transcription factor = square; Node Color: Red indicates increased hazard with high expression, Green indicates decreased hazard with high expression; Node Size: larger indicates a more extreme association (P-value <0.006), smaller indicates a less extreme association.).

Figure 4. Network of microRNA, transcription factors, and target genes associated with ovarian cancer recurrence.

(Node Shape: microRNA = diamond, target gene = circle, transcription factor = square; Node Color: Red indicates increased hazard with high expression, Green indicates decreased hazard with high expression; Node Size: larger indicates a more extreme association (P-value <0.006), smaller indicates a less extreme association.).