4 Patterns of clustered mutational processes: Pan-Cancer analysis of chromothripsis, chromoplexy and kataegis

Abstract

IntroductionSome mutational processes can generate multiple mutations in a single event, leading to substantial reconfiguration of the genome. Three such processes have been described: (i) chromothripsis, in which tens to hundreds of dsDNA breaks occur simultaneously, clustered on one or a few chromosomes, with near-random stitching together of fragments; (ii) chromoplexy, in which repair of co-occurring dsDNA breaks, typically on different chromosomes, results in shuffled chains of rearrangements; and (iii) kataegis, a focal hypermutation process leading to clustered nucleotide substitutions, biassed towards a single DNA strand.Material and methodsWe characterised the Pan-Cancer Analysis of Whole Genomes 2778 cancer genomes for chromothripsis, chromoplexy and kataegis. We refined existing methods and developed novel algorithms for detecting these events, and time their occurrence during tumour evolution.Results and discussionsKataegis was observed in 45.3% of all cancers, particularly in lung squamous cell carcinoma and bladder cancer. The events mostly bore the footprint of APOBEC cytidine deaminases (86.9%). Unexpectedly, 5.3% involved clusters of T>N mutations, often in a TpT or CpT context in tumours of the gastrointestinal tract. In lymphoid tumours, we find hotspots of clustered mutations indicative of off-target activity of AID and Pol. Chromoplexy was observed in 454 samples, frequently involving disease-specific genes. Prostate cancer chains involved TMPRSS2 and ERG. Multiple complex chains were also seen in thyroid cancer, affecting thyroid cancer genes such as IGF2BP3, BRAF and THADA. We identified chromothripsis in 238 samples, most often sarcoma and melanoma. The events manifested in rather different patterns and frequency across tumour types. In stomach cancers, the events were typically limited to a single chromosome, whereas they often involved multiple chromosomes in sarcoma and glioblastoma. Overall, kataegis occurs late during tumour evolution, contributing substantially to subclonal diversification. In contrast, chromothripsis and chromoplexy tended to be clonal. We find early clonal chromothripsis, leading to promoter hijacking by TERT, in a subset of chromophobe kidney cancers. Chromothripsis also occurs early in evolution of several melanomas, enabling rapid amplification of CCND1 with frequent co-involvement of other cancer genes.ConclusionClustered mutational events are widespread across tumour types and can generate multiple drivers as well as enable rapid subclonal diversification.