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Cohn, David Edward

University of British Columbia

Late diagnosis and resistance to targeted therapies are significant obstacles to improving cancer patient outcomes. Many tumours reactivate fetal genes to restore the rapid cell division and migration that occur in development, which makes these genes candidate biomarkers and therapeutic targets. Changes to the expression of microRNAs, which are non-coding RNAs that regulate gene expression, are common in many cancers. Furthermore, most microRNAs can undergo post-transcriptional modifications, which generate functional microRNA variants (isomiRs). I analyzed small RNA sequencing data from fetal and adult human tissues to test the hypothesis that lung adenocarcinoma tumours reactivate fetal microRNAs and isomiRs. First, I compared microRNA expression between adult and fetal lung samples and identified 13 microRNAs that were expressed only in lung adenocarcinoma and the fetal lung, as well as 44 previously unannotated microRNAs. These 13 “oncofetal” microRNAs were predicted to target genes within developmental and cancer-related pathways, and high expression of several oncofetal microRNAs was associated with poor patient outcomes. Additionally, the expression of oncofetal miRNAs distinguished adenocarcinoma and non-malignant samples. I then performed the first characterization of four major types of isomiRs in multiple cohorts of non-malignant lung and lung adenocarcinoma samples. I found that the isomiRome is systemically altered in lung adenocarcinoma, including through changes in miRNA editing and 3’ adenylation rates. The frequencies at which individual microRNAs were post-transcriptionally modified were associated with patient outcomes and distinguished adenocarcinomas from non-malignant samples. Finally, I conducted the first profiling of isomiR expression across six human fetal tissues. Their isomiRomes were largely distinct, and many isomiRs were only expressed in individual tissues. I identified 26 oncofetally-enriched pulmonary isomiRs, and I found that the fetal lung isomiRome overlapped more with the lung adenocarcinoma isomiRome than that of the non-malignant lung. Additionally, rates of microRNA modifications in the fetal lung resembled the altered rates previously observed in lung adenocarcinoma. In this thesis, I show that alterations to the expression and post-transcriptional modification of microRNAs in lung adenocarcinoma restore fetal microRNA and isomiR patterns. Reactivated fetal microRNAs and isomiRs are potential diagnostic biomarkers, and characterization of the mRNAs they regulate may uncover novel therapeutic targets.

Text

2022-09-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/82733

Interdisciplinary Oncology

University of British Columbia

UBCV

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