Abstract 231: MicroRNA isoforms come of age: Going beyond the one-locus-one-microRNA paradigm in cancer biology
Authors: Londin Eric R. , Loher Phillipe , Telonis Aristeidis , Rigoutsos Isidore 
Published: August 2015

Background: MicroRNAs (miRNAs) are short non­coding RNAs that are key post­transcriptional regulators of transcript abundance. During the last decade, their dysregulation has been linked to many human cancers and other human conditions. Similarly to messenger RNAs miRNAs have isoforms (“isomiRs”). In terms of abundance, one of the isomiRs from a given locus typically dominates. In terms of sequence, any two isomiRs from the same locus typically differ by 2-3 nucleotides (nts) at either the 5′ end, the 3′ end, or both. We recently reported on the isomiR profiles (“isomiR-omes”) of lymphoblastoid cell lines (LCLs) derived from ∼500 healthy individuals. We found that each miRNA locus gives rise to multiple isomiRs; often, the most abundant isoform was not the one listed in the miRBase database. Importantly, we demonstrated that many isomiRs exhibited gender-dependent expression whereas other isomiRs exhibited population-dependent or race-dependent expression. Are isomiRs prevalent in the cancer context? And if so, are they relevant? Methods: We analyzed deep sequencing data obtained from healthy and diseased tissues seeking to characterize in each case the respective isomiR-ome by studying all transcribed miRNA loci. The datasets were obtained from The Cancer Genome Atlas (TCGA) repository and included short RNA profiles from breast cancer (BRCA) and other cancers. To investigate isomiR-ome differences between various subsets among the samples we used multivariate statistical analyses. Results: The isomiR-ome differences that we observed in our analyses of LCLs prompted us to extend the analyses to the disease context. Indeed, such isomiR differences can potentially lead to post­transcriptional regulation differences by altering the set of targeted transcripts, especially since isomiRs can differ in their 5´ end. We first analyzed the BRCA TCGA datasets and identified hundreds of distinct and abundant isomiRs. In several instances, a miRNA locus generated between five and ten significantly expressed isomiRs the most abundant of which generally did not match the representative miRBase sequence. Notably, we found that isomiR abundance profiles could distinguish among BRCA subtypes. Also importantly, several isomiRs showed differential expression across racial boundaries. Preliminary analyses of other TCGA cancer datasets led to similar results. Conclusions: Our findings reveal that miRNA isoforms are present and abundant in cancer tissues and differentially expressed among cancer sub-types. This suggests that isomiRs likely play significant roles in the cancer context. Their omni-presence and characteristic expression profiles also suggest that they should be taken into account when studying the miRNA-mediated post-transcriptional regulation layer of cancers. Lastly, our findings also suggest possible uses for isomiRs as molecules for cancer therapeutic and diagnostic purposes.

Citation Format: Eric R. Londin, Phillipe Loher, Aristeidis Telonis, Isidore Rigoutsos. MicroRNA isoforms come of age: Going beyond the one-locus-one-microRNA paradigm in cancer biology. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 231. doi:10.1158/1538-7445.AM2015-231