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The Intra-Tumour Heterogeneity Landscape of Human Cancers 10.17863/CAM.48225 Dentro, Stefan Christiaan Adams, David Van Loo, Peter Wedge, David Tumours accumulate many somatic mutations in their lifetime. Some of these mutations, drivers, convey a selective advantage and can induce clonal expansions. Incomplete clonal expansions give rise to intra-tumour heterogeneity. Somatic mutations can be measured through massively parallel sequencing, where mutations that are supporting incomplete expansions will appear as subclonal. These mutations can be used as a marker of the existence of the expansion and allow for a window into the clonal and subclonal architecture of the tumour at diagnosis. During my Ph.D. I have developed computational methods to infer intra-tumour hetero- geneity from massively parallel sequencing data and applied these to the 2,778 tumour whole genome sequences in the International Cancer Genome Consortium Pan-Cancer Analysis of Whole Genomes initiative to paint the pan-cancer landscape of intra-tumour heterogeneity. I will first introduce the methods; a method to call somatic copy number alterations (Battenberg) and a method to infer subclones from single nucleotide variants (DPClust). Both are extensively validated on simulated and on real data, and I describe a rigorous quality control procedure. The methods are then applied to a single sample to showcase what can be learned about the life history of a cancer, before introducing additional computational methods for a pan-cancer study of heterogeneity. Finally, I describe the findings. I find that nearly all cancers, for which there is sufficient power, contain at least one subclone (96.7% of 1,801 primary tumours). The subclones contain driver mutations that are under positive selection, and known cancer genes contain subclonal driver mutations in low proportions. 9.5% of tumours contain only subclonal drivers that are clinically actionable, suggesting that heterogeneity could inform treatment choices. Finally, the analysis reveals that activity of smoking and UV-light associated mutational signatures goes down as the tumour evolves, while activity of the APOBEC associated signatures goes up. University of Cambridge 2020-01-10 Thesis Doctoral Doctor of Philosophy (PhD) en This thesis was funded by the Wellcome Trust. https://www.repository.cam.ac.uk/handle/1810/301149 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/105edc86-8640-4f1c-8f27-e8e98f295c12/download d9a5a55dc97ca80ca185ff0571022ed2 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/418a7164-cb49-48bc-9c9e-0c9a345762f8/download 87eda9de84448d1f82354d60eee3eb5f https://creativecommons.org/licenses/by-nc-nd/4.0/ Cancer Sequencing Copy Number Alterations Subclonal Architecture