Grigoriadis, Kristiana Karin;
(2025)
Characterising Subclonal Diversification And
Evolutionary Trajectories In Non-small Cell Lung
Cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Tumour evolution fuels genomic intra-tumour heterogeneity (ITH) and metastasis, which is the leading cause of cancer-related mortality. Understanding the underlying genomic instability - including single nucleotide variants (SNVs) and somatic copy number alterations (SCNAs) - driving clonal evolution and metastatic dissemination is crucial for devising effective strategies to prevent and treat metastasis. In this thesis, bulk multi-sample whole-exome sequencing (WES) data from paired primary and metastatic tumours was analysed to explore the co-evolution of SCNAs and SNVs during tumour development in 421 untreated, early-stage non-small cell lung cancers (NSCLC) from the TRACERx study, focusing on identifying genomic processes involved in metastatic seeding. Based on the reconstructed clonal architecture and phylogenetic trees of these cases, subclones under expansion in the primary tumour were shown to have increased evidence of mutational selection. Tumours harbouring more subclonal expansions were associated with metastatic disease and poor patient prognosis. Further, a novel computational method for inferring clone- and allele-specific copy numbers from bulk DNA sequencing data, ALPACA, (ALlele-specific Phylogenetic Analysis of Copy number Alterations) was presented, that leverages the phylogeny reconstructed using SNVs, providing a scalable framework for analysing SCNA and SNV co-evolution. ALPACA accurately reconstructs clone copy number in ground truth data and uncovers SCNAs in minor clones undetectable using sample-level approaches. ALPACA enables the temporal ordering of genomic events. ALPACA reveals recurrent patterns of SCNAs preceding metastatic seeding, including increased chromosomal instability, enrichment for loss-of-heterozygosity affecting combined tumour suppressor genes, and enrichment for focal SCNAs including SMARCA4 loss and CCND1 and MYC amplification. Finally, higher clone copy number diversity was associated with poorer disease-free survival. Together, these results suggest that increased subclonal expansions and CIN in the primary tumour drive a metastatic phenotype, and emphasise the importance of phylogeny-aware analyses of sequencing data to explore the prognostic impact of ITH.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Characterising Subclonal Diversification And Evolutionary Trajectories In Non-small Cell Lung Cancer |
| 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 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/10203285 |
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