Pan-cancer characterisation of microRNA with hallmarks of cancer reveals role of microRNA-mediated downregulation of tumour suppressor genes

Abstract

microRNA are key regulators of the human transcriptome across a number of diverse biological processes, such as development, aging, and cancer, where particular miRNA have been identified as tumour suppressive and oncogenic. In this work, we sought to elucidate, in a comprehensive manner, across 15 epithelial cancer types comprising 7,316 clinical samples from the Cancer Genome Atlas, the association of miRNA expression and target regulation with the pheno-typic hallmarks of cancer. Utilising penalized 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.