Pan-cancer characterisation of microRNA across cancer hallmarks reveals microRNA-mediated downregulation of tumour suppressors

Abstract

microRNAs are key regulators of the human transcriptome across a number of diverse biological processes, such as development, aging and cancer, where particular miRNAs have been identified as tumour suppressive and oncogenic. In this work, we elucidate, in a comprehensive manner, across 15 epithelial cancer types comprising 7316 clinical samples from the Cancer Genome Atlas, the association of miRNA expression and target regulation with the phenotypic hallmarks of cancer. Utilising penalised regression techniques to integrate transcriptomic, methylation and mutation data, we find evidence for a complex map of interactions underlying the relationship of miRNA regulation and the hallmarks of cancer. This highlighted high redundancy for the oncomiR-1 cluster of oncogenic miRNAs, in particular hsa-miR-17-5p. In addition, we reveal extensive miRNA regulation of tumour suppressor genes such as PTEN, FAT4 and CDK12, uncovering an alternative mechanism of repression in the absence of mutation, methylation or copy number changes.