Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

Erik N. Bergstrom, Jens Luebeck, Mia Petljak, Azhar Khandekar, Mark Barnes, Tongwu Zhang, Christopher D. Steele, Nischalan Pillay, Maria Teresa Landi, Vineet Bafna, Paul S. Mischel, Reuben S. Harris and Ludmil B. Alexandrov ()
Additional contact information
Erik N. Bergstrom: University of California San Diego
Jens Luebeck: University of California San Diego
Mia Petljak: Broad Institute of MIT and Harvard
Azhar Khandekar: University of California San Diego
Mark Barnes: University of California San Diego
Tongwu Zhang: National Cancer Institute
Christopher D. Steele: University College London
Nischalan Pillay: University College London
Maria Teresa Landi: National Cancer Institute
Vineet Bafna: University of California San Diego
Paul S. Mischel: Stanford University School of Medicine
Reuben S. Harris: University of Minnesota
Ludmil B. Alexandrov: University of California San Diego

Nature, 2022, vol. 602, issue 7897, 510-517

Abstract: Abstract 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 substitutions1–5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7–9. 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 cancer10. 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 either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, 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 of APOBEC3 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.

Date: 2022
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DOI: 10.1038/s41586-022-04398-6

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