Identification of miRNA-Mediated Subpathways as Prostate Cancer Biomarkers Based on Topological Inference in a Machine Learning Process Using Integrated Gene and miRNA Expression Data

Abstract

Accurately identifying classification biomarkers for distinguishing between normal and cancer samples is challenging. Additionally, the reproducibility of single-molecule biomarkers is limited by the existence of heterogeneous patient subgroups and differences in the sequencing techniques used to collect patient data. In this study, we developed a method to identify robust biomarkers (i.e., miRNA-mediated subpathways) associated with prostate cancer based on normal prostate samples and cancer samples from a dataset from The Cancer Genome Atlas (TCGA; n = 546) and datasets from the Gene Expression Omnibus (GEO) database (n = 139 and n = 90, with the latter being a cell line dataset). We also obtained 10 other cancer datasets to evaluate the performance of the method. We propose a multi-omics data integration strategy for identifying classification biomarkers using a machine learning method that involves reassigning topological weights to the genes using a directed random walk (DRW)-based method. A global directed pathway network (GDPN) was constructed based on the significantly differentially expressed target genes of the significantly differentially expressed miRNAs, which allowed us to identify the robust biomarkers in the form of miRNA-mediated subpathways (miRNAs). The activity value of each miRNA-mediated subpathway was calculated by integrating multiple types of data, which included the expression of the miRNA and the miRNAs’ target genes and GDPN topological information. Finally, we identified the high-frequency miRNA-mediated subpathways involved in prostate cancer using a support vector machine (SVM) model. The results demonstrated that we obtained robust biomarkers of prostate cancer, which could classify prostate cancer and normal samples. Our method outperformed seven other methods, and many of the identified biomarkers were associated with known clinical treatments.