Ding, Chuling;
(2023)
Development and application of phylogenetic methods for copy-number analysis in cancer evolution: from methylation arrays to bulk and single cell sequencing data.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
Thesis_all_formatted_submission_Clean.pdf - Accepted Version Download (14MB) | Preview |
Abstract
Copy number aberrations (CNAs) have long been recognised as hallmarks of many cancer types and driving forces of intra-tumour heterogeneity (ITH). Nevertheless, most of existing computational methods for copy number analysis consider independent samples only and require high sequencing depth, posing critical challenges on interpretating CNAs in an accurate and cost-efficient context. Apart from methylation patterns, methylation arrays also permit inferring copy number (CN) profiles. The first part of this thesis introduces two computational tools based on methylation array data: 1) MAACnR (Methylation Array Absolute Copy number Rescaling) to rescale and call absolute CN (ACN) states from LogR ratios and 2) MultiSEPhyR (Multi-Sample EPIC Phylogenetic Reconstruction) to deconvolve clonal composition and infer clonal phylogenies based on multiple related CN profiles. As part of the GCGR (Glioma Cellular Genetic Resource; gcgr.org.uk) project, we profile 58 pairs of primary glioblastomas (GBM) and their derived glioma stem cell (GSC) lines and compare the copy number landscape across different subtypes. By assessing clonal composition in GBM-GSC pairs, we report an overall conservation of ITH in GBM-GSC pairs across the cohort. We also observe recurrent copy number events specific to in vitro or in vivo samples, and a positive association between the similarity of GBM-GSC pairs and the aggressiveness of the GSC lines. In the second part of this thesis, we investigate evolutionary trajectories of leukaemia from two case studies by applying a collection of cutting-edge multi-sample approaches. We characterise a major clone that is marked by multiple genomic aberrations in one patient and a potentially bi-phenotypic clone in the other. Finally, we discuss challenges and propose solutions in the analysis of single cell WGS data for the correct interpretation of copy number events. To summarise, this thesis demonstrates the capacity of phylogenetic methods for the interpretation of cancer evolution, irrespective of the data type.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Development and application of phylogenetic methods for copy-number analysis in cancer evolution: from methylation arrays to bulk and single cell sequencing data |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. 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 Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10178920 |
Archive Staff Only
 |
View Item |
