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Timing Genetic Events in Tumours with Chromosomal Instability

Baker, Toby M.; (2024) Timing Genetic Events in Tumours with Chromosomal Instability. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Tumours develop through a series of somatic events. The genome sequence of a tumour provides a partial record of the events that have occurred in its development. Here, I develop two new bioinformatic methods, GRITIC and GRITIC-SNV, that infer the timing of copy number gains and single nucleotide variants (SNVs) from the whole genome sequence of a tumour. I apply these tools to 7,013 tumours to understand the genetic development of primary and metastatic tumours in a pan-cancer setting. GRITIC provides a generic framework to time gains that lead to complex copy number states. It uses a novel tree-based representation to enumerate and time possible route histories that can lead to a copy number state. I use GRITIC to test the assumption of parsimonious copy number evolution in genome duplicated tumours and find that it is frequently violated. I measure chromosomal instability before and after whole genome duplication (WGD). Late WGDs are followed by an immediate increase in the rate of gains. While the selection landscape of copy number events is generally conserved following a WGD, a number of specific genomic regions are found to have a disproportionate frequency of events pre-WGD, particularly losses. GRITIC-SNV is a generic method to quantitatively time SNV in the clonal evolutionary period. I apply it to consider the timing of driver SNVs in PCAWG and Hartwig. I then extend the framework to time mutational signatures and find that, as expected, environmentally associated mutations are associated with early tumour development. I also find evidence of episodic APOBEC mutagenesis across many tumours and clear timing patterns in many mutational processes that have unknown origins. To summarise, GRITIC and GRITIC-SNV increase the evolutionary information that can be obtained from tumour genome sequences and, therefore, improve our understanding of the developmental history of cancer.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Timing Genetic Events in Tumours with Chromosomal Instability
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10187547
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