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, Ludmil B. Alexandrov

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)510-517
Number of pages8
JournalNature
Volume602
Issue number7897
DOIs
StatePublished - Feb 17 2022

Bibliographical note

Funding Information:
E.N.B. and L.B.A. were supported by the Cancer Research UK Grand Challenge Award C98/A24032 as well as US National Institute of Health (NIH) grants R01ES030993-01A1 and R01ES032547. L.B.A. is an Abeloff V Scholar and he was also supported by an Alfred P. Sloan Research Fellowship. Research at the University of California San Diego was also supported by a Packard Fellowship for Science and Engineering to L.B.A. N.P. is funded through a Cancer Research UK grant (grant no. 18387) and is supported by the UCLH Biomedical Research Centre and the Cancer Research UK Experimental Cancer Centre. C.D.S. is funded through Cancer Research UK and the Neurofibromatosis Research Initiative (NFRI) at Boston Children’s Hospital–GeM consortium. M.P. is supported by a European Molecular Biology Organization (EMBO) Long-Term Fellowship (ALTF 760-2019). V.B. and J.L. were supported in part by grants U24CA264379 and R01GM114362 from the NIH. P.S.M. is supported in part by grants U24CA264379 and RO1CA238249 from the NIH. Cancer research in the R.S.H. laboratory is supported by NCI grant P01CA234228. R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor and an Investigator of the Howard Hughes Medical Institute. The funders had no roles in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funding Information:
E.N.B. and L.B.A. were supported by the Cancer Research UK Grand Challenge Award C98/A24032 as well as US National Institute of Health (NIH) grants R01ES030993-01A1 and R01ES032547. L.B.A. is an Abeloff V Scholar and he was also supported by an Alfred P. Sloan Research Fellowship. Research at the University of California San Diego was also supported by a Packard Fellowship for Science and Engineering to L.B.A. N.P. is funded through a Cancer Research UK grant (grant no. 18387) and is supported by the UCLH Biomedical Research Centre and the Cancer Research UK Experimental Cancer Centre. C.D.S. is funded through Cancer Research UK and the Neurofibromatosis Research Initiative (NFRI) at Boston Children?s Hospital?GeM consortium. M.P. is supported by a European Molecular Biology Organization (EMBO) Long-Term Fellowship (ALTF 760-2019). V.B. and J.L. were supported in part by grants U24CA264379 and R01GM114362 from the NIH. P.S.M. is supported in part by grants U24CA264379 and RO1CA238249 from the NIH. Cancer research in the R.S.H. laboratory is supported by NCI grant?P01CA234228. R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor and an Investigator of the Howard Hughes Medical Institute. The funders had no roles in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2022, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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