Journal
NATURE
Volume 602, Issue 7897, Pages 510-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04398-6
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Funding
- Cancer Research UK Grand Challenge Award [C98/A24032]
- US National Institute of Health (NIH) [R01ES030993-01A1, R01ES032547]
- Alfred P. Sloan Research Fellowship
- Packard Fellowship for Science and Engineering
- Cancer Research UK [18387]
- UCLH Biomedical Research Centre
- Cancer Research UK Experimental Cancer Centre
- Cancer Research UK
- Neurofibromatosis Research Initiative (NFRI) at Boston Children's Hospital-GeM consortium
- European Molecular Biology Organization (EMBO) Long-Term Fellowship [ALTF 760-2019]
- NIH [U24CA264379, R01GM114362, RO1CA238249]
- NCI [P01CA234228]
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This study provides a comprehensive characterization of clustered mutations and small insertions and deletions in cancer genomes. The results show that clustered mutations are enriched in driver genes and associated with differential gene expression and overall survival. Different mutational processes contribute to clustered insertions and deletions, including specific signatures in tobacco smokers and homologous-recombination-deficient cancers. APOBEC3 plays a significant role in clustered substitutions, although only a small percentage matches APOBEC3 patterns. The study also reveals the associations between the activation-induced deaminase (AID) and APOBEC3 family of deaminases with kataegis (longer strand-coordinated events).
Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions(1-5), diffuse hypermutation termed omikli(6), and longer strand-coordinated events termed kataegis(3,7-9). Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer(10). Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by eithertobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity(6), accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence ofAPOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.
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