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.
Highlights
Ovarian cancer, the most malignant gynecologic neoplasm, is the fifth leading cause of cancer deaths among women
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
The expression of three miRNAs, four Transcription factors (TFs) (FOS, EGR2, EGR1, and TGFB1) and 308 genes were associated with the hazard of ovarian cancer survival and recurrence
Summary
The most malignant gynecologic neoplasm, is the fifth leading cause of cancer deaths among women. Few gene expression profiles have been consistently related to ovarian cancer [2,3]. This may be due to the limited simultaneous consideration of the transcripts and transcript regulators associated with ovarian cancer. MicroRNAs (miRNAs) are small, non-coding RNA molecules that bind to complementary sequences on target mRNA transcripts, and regulate gene expression at the posttranscription stage. Transcription factors (TFs) are a different type of regulator. These proteins bind to specific DNA sequences in the promoter region, promoting or repressing transcription into mRNA, and regulate genes at a pre-transcription stage [4]. TF-miRNA-target genes can function as onco or tumor suppressor networks, triggering global alterations of genetic programs implicated in cell proliferation, differentiation, apoptosis, and invasiveness in cancer
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