Pawlik, Piotr;
(2025)
Inference of clone-specific copy numbers from bulk tumour DNA.
Doctoral thesis (Ph.D), UCL (University College London).
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Thesis_PHD_Piotr_Pawlik.pdf - Accepted Version Access restricted to UCL open access staff until 1 August 2025. Download (29MB) |
Abstract
Cancer is an evolutionary process. During this process, single nucleotide variants (SNVs) and somatic copy-number alterations (SCNAs) accumulate, contributing to clonal evolution. Nevertheless, making accurate inferences about their co-evolution and clone-specific copy numbers from bulk DNA sequencing poses a significant challenge. In this thesis, I present ALPACA (ALlelespecific Phylogenetic Analysis of clone Copy-number Alterations), a computational method which allows inference of clone-specific copy-numbers from bulk DNA by leveraging phylogenetic trees and SNV cellular frequencies obtained from multi-sample sequencing experiments. I validate this approach with two simulated tumour cohorts and with single-cell data, comparing the ALPACA output both with the ground truth and with the outputs of two previously published methods. I then apply ALPACA to the TRACERx421 (TRAcking non-small cell lung Cancer Evolution through therapy Frankell et al. 2023; Al Bakir et al. 2023) cohort and demonstrate that ALPACA can identify loss-ofheterozygosity events and amplifications in minor metastasis seeding clones, not detectable on bulk-sample copy-number level. By comparing seeding and non-seeding clones within the primary-metastatic matched cohort I observe evidence of increased chromosomal instability in metastasis seeding clones. Using ALPACA’s clone-specific copy-numbers I develop a novel method to quantify intra-tumour copy-number heterogeneity: clone copy-number diversity (CCD). Using this metric I show that patients who later develop a metastatic disease harbour a higher intra-tumour clone copy number diversity within their primary tumours compared to patients who do not relapse. Lastly, I show an association between CCD and patient survival.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Inference of clone-specific copy numbers from bulk tumour DNA |
| Language: | English |
| Additional information: | Copyright © The Author 2025. 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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203239 |
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