Watkins, Thomas Benjamin Kingdon; (2020) The role of chromosomal instability and parallel evolution in cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Although chromosomal instability (CIN) is recognised as an initiating process in cancer, the extent and relevance of ongoing somatic copy number alterations (SCNAs) that result from it later in tumour development is unclear. In this thesis I describe a comprehensive analysis, including 1421 tumour samples (394 patients; 22 tumour types), to evaluate ongoing CIN and SCNAs in tumour evolution and show that intratumor heterogeneity mediated through chromosomal instability is associated with an increased risk of recurrence or death in non-small cell lung cancer (NSCLC), a finding that supports the potential value of CIN as a prognostic predictor. I also uncover pervasive SCNA intratumour heterogeneity across cancers, with recurrent clonal and subclonal events identified and found to demonstrate enrichment for cancer genes. I develop novel techniques for obtaining a phasing of heterozygous SNPs from multi-region next generation sequencing data and apply them to observe recurrent parallel evolutionary events converging upon disruption to the same genes in distinct subclones within 146 individual tumours. The most prevalent recurrent parallel loss event involved chromosome 14, including HIF1A and HIF1B. In addition, chromosome 5p, including TERT, was recurrently gained and subject to parallel evolution in 7 tumour types. Tumour type-specific constraints to early tumour development were identified in the form of obligatory clonal LOH, including LOH of 3p in clear cell renal cell carcinoma, lung squamous cell carcinoma (LUSC) and triple-negative breast cancer and LOH of 17p in LUSC, colorectal adenocarcinoma, triple negative and HER2+ breast cancer. Wholegenome doubling (WGD) was generally an early event in tumour evolution, associated with an increased acquisition of both clonal and subclonal SCNAs. For instance, CCNE1 amplifications, which occurred exclusively in WGD tumours, were subclonal in 45% of these cases, suggesting this event may be selected following a WGD event. Mathematical modelling of subclonal SCNA evolution demonstrated that models that incorporate ongoing selection with respect to SCNAs significantly outperform evolutionary neutral models, particularly in the context of WGD. This thesis highlights the importance of ongoing CIN and recurrent subclonal chromosomal alterations in tumour evolution, reveals parallel evolution of SCNAs, and sheds light on the dynamics and order of events that influence metastasis.

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