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UBC Theses and Dissertations

Non-coding RNA expression in lung adenocarcinoma : the long and the short of it Sage, Adam Patrick


Lung cancer genomic profiling has led to the development of therapies targeting aberrant protein expression. However, the majority of patients present tumours with undruggable or unidentified driver mutations, highlighting the need for a new approach to discover lung cancer genes. Non-coding RNAs (ncRNAs) have emerged as critical regulators of cellular processes, such as proliferation, apoptosis, and the immune response; functions that can be perturbed in cancer. I take a global approach to explore the broad role of ncRNAs in lung tumours to uncover alternative regulatory mechanisms and potential therapeutic targets. Non-coding RNAs are divided into two main categories based on their size: small (sncRNAs; <200nt) and long (lncRNAs; >200nt). I analyzed small RNA sequencing data from two cohorts of paired lung tumour and non-malignant tissue samples to identify previously-unannotated microRNAs (miRNAs). Using in silico algorithms and subsequent curation, I discovered 141 novel miRNA sequences, representing a substantial increase in the lung miRNA transcriptome. Not only were these transcripts specifically expressed in lung tissues, but they also displayed deregulated expression patterns in tumours and potential prognostic value. This strategy has been instrumental for miRNA discovery in tumours from other organs. Immunotherapy has provided a promising treatment option for lung cancer, but the ability to predict treatment response is an emerging challenge. LncRNAs are known to have a significant role in the immune system. Several lncRNAs have described functions in lung tumours, but lncRNA expression in tumour-infiltrating lymphocytes remains uncharacterized. I determined the lncRNA expression patterns from purified human immune cell subsets, and delineated their cell-type specificity, which may contribute to their particular immune-regulatory roles. These expression patterns were recapitulated in both bulk lung and in single-cell RNA sequencing data. My observations highlight the contribution of infiltrating immune cells to sequencing analyses and also the relevance of lncRNAs to the biology of the tumour microenvironment. Together, my results emphasize the importance of high-throughput deep-sequencing efforts and lay a foundation for the discovery of novel genes involved in lung cancer biology. Assessment of ncRNAs represents the next frontier of cancer biology research and new opportunities for therapeutic target and biomarker discovery.

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