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miRNA sequence analysis reveals cancer subtypes that correlate with tumour characteristics and patient outcomes

University of British Columbia

microRNAs (miRNAs) are small 17-25nt RNA molecules that regulate gene expression at the post-transcriptional level. A given miRNA may have up to several hundred gene targets, and 60% of messenger RNAs (mRNAs) have binding sites for multiple miRNAs in their 3’- untranslated regions (UTRs). miRNAs have been implicated in the regulation of numerous biological processes, including cellular growth, differentiation and apoptosis, and miRNA dysregulation has been associated with diseases including cancers. miRNAs are stable and robust in a variety of fresh and preserved human tissues, and thus are useful in disease classification and subtype identification. They have also been used to infer dysregulation of regulatory pathways. With the aims of identifying cancer subtypes and relating these to clinical covariates and studying miRNA-mediated regulation, I analyzed miRNA-seq and mRNA-seq expression profiles from diffuse large B-cell lymphomas (DLBCL), pediatric acute myeloid leukemias (AML) and pediatric malignant rhabdoid tumours (MRT). My analyses provided comprehensive characterization of miRNA expression profiles, revealed molecular sub-groups within cancer types, novel miRNA species, putative miRNA prognostic markers, and candidate functional miRNA:mRNA interactions. Of note, I discovered a novel miRNA (miR-10393-3p) that was preferentially expressed in DLBCL samples, and further revealed that it could target genes involved in chromatin modification. I also found that the miR-106a-363 cluster was not only significantly associated with inferior patient outcomes in pediatric AML, but may also contribute to treatment resistance by modulating the expression of genes involved in oxidative phosphorylation. In addition, I performed hierarchical clustering of MRT miRNA profiles together with those of 11,753 other samples representing 36 cancer types and 26 normal tissue types. This analysis demonstrated that MRT samples are most similar to cerebellum and DLBCL samples, possibly reflecting a related cell of origin as these samples. Overall, the research presented in this thesis constitutes a step forward in our understanding of miRNA dysregulation within cancer types and identifies miRNAs that could be useful prognostic markers in guiding treatment selection.

Text

2017-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/57440

Bioinformatics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/