Dietzen, Michelle; (2023) Investigating somatic mutational processes over time and space. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cancer is an evolutionary disease in which the accumulation of mutations during each cell cycle provides the fuel for shaping the evolutionary trajectories of a tumour. Somatic mutations are not accumulated equally across the genome. Instead, epigenetic features, such as DNA replication timing, relate to variations in the mutation frequency along the genome. Here, I set out to investigate the impact of variations in DNA replication timing on the accumulation of mutations across the genome and the dynamics of mutagenic processes shaping a tumour’s evolutionary trajectory. Investigating patterns in the mutation frequencies across the genome, in form of the extraction of mutation distribution signatures, revealed clear differences between lung cancer subtypes. These differences were not only due to variations in the distribution of epigenetic features in the corresponding cell-of- origin, but likely related to a change in the epigenetic landscape during malignant transformation. Comparing the replication timing program of cancer cells to their cell-of-origin uncovered replication timing alterations occurring during malignant transformation. These alterations were found to be recurrent within breast and lung cancer subtypes. Replication timing alterations were found to impact the accumulation of mutations, including the activity of DNA damage and repair mechanisms, during cancer evolution. Furthermore, the extent to which replication timing alterations affect the likelihood of mutation acquisition in different regions of the genome was leveraged to estimate their relative timing of occurrence during tumour development. While replication timing alterations were found to occur early relative to mutation accumulation during tumour development in breast cancer and lung adenocarcinomas, their relative timing was estimated to be late in lung squamous cell carcinomas. To better understand the dynamics of mutational processes that were active throughout a tumour’s lifetime, a method to estimate the activity of mutational processes along the different evolutionary trajectories of a tumour was developed and applied to the multi-region sequenced TRACERx non-small-cell lung cancer tumours. This method provided the opportunity to discover complex activity patterns contributing to the diversification of a tumour. This thesis demonstrates the impact of variations in the replication timing on the accumulation of mutations across the genome and the complex dynamics of mutagenic processes active during tumour evolution. These observations contribute to resolving the genetic heterogeneity in cancer which may improve targeted therapies leading to an advancement in a patient’s outcome.

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