On the causation and timing of mutations during cancer evolution

Mutations are the proximal causes of cancer and of drug resistance. Better understanding the causation of mutations before and during cancer can open up avenues for improved cancer prevention and treatment. Early mutations may be of particular interest for therapeutic targeting and early detection. In Chapter 2, I use a mathematical model of breast cancer development to assess the hypothesis that varying numbers of progenitor cells causes a slow-down in mutation accumulation. In Chapter 3, I present an adapted method to time the accumulation of copy number changes using sequencing data, and an application of this method in colorectal cancer. This application supports the hypothesis of a catastrophic process where multiple copy number alterations develop at the same time in colorectal cancer. In Chapter 4, I present evidence that a mutational process linked to defects in the POLE gene causes key driver mutations in colorectal and endometrial cancer. Based on this evidence and other analyses I argue that POLE mutations are very early events in colorectal and endometrial cancer. In Chapter 5, I build on the ideas presented in Chapter 4 to assess the causation of driver mutations by mutational processes in a pan-cancer analysis. These results suggest causal explanations for key driver mutations in terms of mutational processes, and shed light on the important underlying biology of selection of driver mutations. In whole my work expands our knowledge of the effects of mutational processes on cancer mutations and the timing of these mutations, indicates research strategies for novel approaches to cancer prevention and treatment, and informs our understanding of the biological context of cancer evolution