Abstract
Cancer is a disease of the genome, but the dramatic inter-patient variability in mutation number is poorly understood. Tumours of the same type can differ dramatically in their mutation rate. To improve our understanding of potential drivers and the consequences of the underlying heterogeneity in mutation rate across tumours, we evaluated both local and global measures of mutation density (both single-stranded and double-stranded DNA breaks) in 2,460 tumours across 38 cancer types. We find that SCNAs in thousands of genes are associated with elevated rates of point-mutations, while conversely, SNVs in dozens of genes are associated with specific patterns of DNA double-stranded breaks. To supplement this understanding of global mutation density, we developed and validated a tool called SeqKat to identify localized regions of hypermutation (also known as kataegis). We show that rates of kataegis differ by four orders of magnitude across tumour types and that tumours with TP53 point mutations were 2.6-times more likely to harbour a kataegic event than those without. Furthermore, we identify novel subtypes of kataegic events not associated with aberrant APOBEC activity and found that kataegic events were associated with patient survival in some, but not all tumour types. Taken together, we reveal a landscape of genes driving localized and tumour-specific hyper-mutation, and reveal novel mutational processes at play in specific tumour types.
