eprintid: 10203239
rev_number: 13
eprint_status: archive
userid: 699
dir: disk0/10/20/32/39
datestamp: 2025-03-14 13:46:45
lastmod: 2025-03-14 13:46:45
status_changed: 2025-03-14 13:46:45
type: thesis
metadata_visibility: show
sword_depositor: 699
creators_name: Pawlik, Piotr
title: Inference of clone-specific copy numbers from bulk tumour DNA
ispublished: unpub
divisions: UCL
divisions: B02
divisions: C10
divisions: D19
divisions: G99
note: 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.
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.
date: 2025-01-28
date_type: published
full_text_type: other
thesis_class: doctoral_embargoed
thesis_award: Ph.D
language: eng
verified: verified_manual
elements_id: 2352203
lyricists_name: Pawlik, Piotr
lyricists_id: PPAWL31
actors_name: Pawlik, Piotr
actors_id: PPAWL31
actors_role: owner
full_text_status: restricted
pages: 207
institution: UCL (University College London)
department: UCL Cancer Institute
thesis_type: Doctoral
citation:        Pawlik, Piotr;      (2025)    Inference of clone-specific copy numbers from bulk tumour DNA.                   Doctoral thesis  (Ph.D), UCL (University College London).    
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10203239/5/Thesis_PHD_Piotr_Pawlik.pdf