Investigating the role of non-coding mutations in cancer.

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Embargoed until 2019-04-30
Copyright: Perera, Dilmi
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Abstract
Whole genomes are being sequenced at an accelerated pace but research into cancer causing mutations has focused primarily on protein-coding mutations owing to difficulties associated with identifying and interpreting causality of noncoding mutations. Nevertheless, projects such as ENCODE and the Epigenome Atlas have led to the generation of genome-wide datasets that have contributed to our understanding of the noncoding parts of the human genome. The integration of these datasets has the potential to shed light on the functions of noncoding sequences, gene regulatory modules and epistatic interactions underlying disease associations. Moreover, through technological advances it is now feasible to routinely sequence whole genomes of cancer samples which has enable large international consortiums such as TCGA and ICGC to create public datasets consisting of mutations from whole genome sequencing of 1000s of tumour samples. The integrative analyses of datasets from these resources have provided new opportunities to interrogate non-coding cancer mutations. In order to elucidate the role of cis-regulatory mutations in cancer, I developed an annotation method and web tool to study the effect of cis-regulatory mutations in cancer and to identify potential causal mutations for further investigations. Applying this tool to whole breast cancer genome sequencing data, I discovered a point mutation in the enhancer of CDK6 that results in the overexpression of the gene. I then conducted a pan-cancer analysis of cis-regulatory mutations using somatic mutations from 1161 whole tumour genomes across 14 cancer types from publicly available data sources which revealed a previously unknown mechanism linking transcription initiation and NER as a major contributor of somatic point mutation hotspots at active gene promoters in cancer genomes. In the final chapter of the thesis, I examined cancer mutations in non-coding RNA and their effect on structure and function. Through this thesis, I have been able to significantly contribute to our understanding of non-coding or regulatory regions of the genome and the role of mutations in these regions in cancer and to develop computational methods and tools to assist experimentalists to further explore this field of science.
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Author(s)
Perera, Dilmi
Supervisor(s)
Wong, Jason
Pimanda, John
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Publication Year
2017
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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