Cresswell, George David; (2018) A Genomic Study of the Evolution of Paediatric Solid Tumours. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Paediatric cancers evolve very differently to adult cancers: they develop over months, not decades, and are exposed to few exogenous mutagens. Despite major strides in our understanding of adult cancers, little is known about the evolutionary trajectories of paediatric solid cancers. This thesis focuses on the commonest paediatric malignancies of the kidney and liver to determine their genetic past. Constructing the evolutionary history of a cancer requires estimating the number of cells possessing each mutation in a tumour and determining their ordering. In the first part of the thesis, I compare copy number alterations (CNAs) in multiple tumour regions to construct the histories of 20 Wilms’ tumours (WTs). I uncover patterns of CNA occurrence, describe their role in the different stages of tumorigenesis, and relate phylogeny to clinically important features. In the second part, I develop a method to estimate cellular proportion of CNAs by modelling heterozygous single nucleotide polymorphisms from array data as a Gaussian mixture. By determining the composition of spatially separate and locally mixing clones, I perform a comprehensive reconstruction of the evolutionary histories of >70 WTs and 11 hepatoblastomas. Supporting my analysis using targeted sequencing of ~180 genes, I show that convergent evolution of CNAs and single nucleotide variation highlights contextdependent selection. I discover subtype-specific features of WT evolution, including a consistent trajectory of stromal WT evolution. Finally, I show CNA instability as a potential biomarker in WT, suggesting that burden of CNAs may identify highrisk patients. In summary, this thesis describes the diversity of evolution in two paediatric solid cancers and novel approaches to studying these diseases. By uncovering evidence for how these cancers evolve over time, I gain insights into the sequential genetic changes that form the histories of these cancers and demonstrate the clinical relevance both in terms of sub-type diagnosis and prognosis.

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