The sequencing of cancer genomes has revealed that cancers harbour recurrent patterns of mutation, known as mutational signatures. One common mutational signature, known as the APOBEC signature, is found in over 70% of cancer types. The APOBEC signature is thought to be mediated by the activity of the APOBEC enzyme family. However, the underlying cause of APOBEC activity in cancer is not fully understood.

This thesis investigates the regulation of APOBEC mutagenesis in cancer. There is a focus on APOBEC3A and APOBEC3B as likely mediators of APOBEC signature mutations, and a focus on the hypothesis that APOBEC activity might be driven by the activity of LINE-1 retrotransposons.

Firstly, the thesis details experiments to investigate APOBEC activity in cultured cancer cells. The experiments conducted suggest that p53 inactivation leads to the upregulation of LINE-1 and APOBEC3B, and that their expression may be downregulated when p53 activity is promoted. An enzymatic assay for cancer-associated APOBEC activity is established. Reverse transcriptase inhibitors, which inhibit LINE-1 activity, appear to modulate APOBEC3B expression and associated enzymatic activity. This appears to occur when cells are p53-deficient, but not when p53 is intact.

Secondly, the thesis reports exploratory bioinformatic analyses conducted using large genomic datasets. These indicate that APOBEC3A expression is associated with interferon signalling in cancer while APOBEC3B expression is associated with cell cycle signalling in cancer. A deletion of a consensus interferon response factor binding site in the APOBEC3B promoter is identified. Analyses of regulatory data suggest that APOBEC3B might be transcriptionally insulated from syntenic APOBEC3 genes by CTCF. In addition, p53 deficiency in cancer appears to be associated with the upregulation of APOBEC3A and APOBEC3B.

Thirdly, the thesis reports bioinformatic analyses of an RNA sequencing dataset from patients with the rare genetic disease Aicardi-Goutières syndrome. It is thought that the disease process of the genotypes studied might driven by LINE-1 activity, as suggested in part by successful patient trials of reverse transcriptase inhibitors. The analyses conduced appear to identify changes to the transcriptome in Aicardi-Goutières syndrome that might mirror those associated with APOBEC activity in cancer.

In sum, these experiments provide evidence for possible regulators of APOBEC mutagenesis in cancer, including evidence that broadly supports the hypothesis that it may be driven by LINE-1 activity. The experiments also identify a class of drugs that might enable the pharmacological modulation of cancer-associated APOBEC activity. APOBEC mutagenesis is thought to mediate cancer initiation, progression, intratumour heterogeneity and responses to therapy, including immunotherapy. The findings detailed might therefore contribute to the ability to understand and control the natural history of cancer across multiple cancer types.