Genome-wide cross-cancer analysis illustrates the critical role of bimodal miRNA in patient survival and drug responses to PI3K inhibitors

Abstract

Heterogeneity of cancer means many tumorigenic genes are only aberrantly expressed in a subset of patients and thus follow a bimodal distribution, having two modes of expression within a single population. Traditional statistical techniques that compare sample means between cancer patients and healthy controls fail to detect bimodally expressed genes. We utilize a mixture modeling approach to identify bimodal microRNA (miRNA) across cancers, find consistent sources of heterogeneity, and identify potential oncogenic miRNA that may be used to guide personalized therapies. Pathway analysis was conducted using target genes of the bimodal miRNA to identify potential functional implications in cancer. In vivo overexpression experiments were conducted to elucidate the clinical importance of bimodal miRNA in chemotherapy treatments. In nine types of cancer, tumors consistently displayed greater bimodality than normal tissue. Specifically, in liver and lung cancers, high expression of miR-105 and miR-767 was indicative of poor prognosis. Functional pathway analysis identified target genes of miR-105 and miR-767 enriched in the phosphoinositide-3-kinase (PI3K) pathway, and analysis of over 200 cancer drugs in vitro showed that drugs targeting the same pathway had greater efficacy in cell lines with high miR-105 and miR-767 levels. Overexpression of the two miRNA facilitated response to PI3K inhibitor treatment. We demonstrate that while cancer is marked by considerable genetic heterogeneity, there is between-cancer concordance regarding the particular miRNA that are more variable. Bimodal miRNA are ideal biomarkers that can be used to stratify patients for prognosis and drug response in certain types of cancer.