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Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair

Author

Listed:
  • N. J. Haradhvala

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT)

  • J. Kim

    (Broad Institute of Harvard and MIT)

  • Y. E. Maruvka

    (Broad Institute of Harvard and MIT)

  • P. Polak

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    Harvard Medical School)

  • D. Rosebrock

    (Broad Institute of Harvard and MIT)

  • D. Livitz

    (Broad Institute of Harvard and MIT)

  • J. M. Hess

    (Broad Institute of Harvard and MIT)

  • I. Leshchiner

    (Broad Institute of Harvard and MIT)

  • A. Kamburov

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    Harvard Medical School)

  • K. W. Mouw

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • M. S. Lawrence

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    Harvard Medical School)

  • G. Getz

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    Harvard Medical School)

Abstract

Fidelity of DNA replication is maintained using polymerase proofreading and the mismatch repair pathway. Tumors with loss of function of either mechanism have elevated mutation rates with characteristic mutational signatures. Here we report that tumors with concurrent loss of both polymerase proofreading and mismatch repair function have mutational patterns that are not a simple sum of the signatures of the individual alterations, but correspond to distinct, previously unexplained signatures: COSMIC database signatures 14 and 20. We then demonstrate that in all five cases in which the chronological order of events could be determined, polymerase epsilon proofreading alterations precede the defect in mismatch repair. Overall, we illustrate that multiple distinct mutational signatures can result from different combinations of a smaller number of mutational processes (of either damage or repair), which can influence the interpretation and discovery of mutational signatures.

Suggested Citation

  • N. J. Haradhvala & J. Kim & Y. E. Maruvka & P. Polak & D. Rosebrock & D. Livitz & J. M. Hess & I. Leshchiner & A. Kamburov & K. W. Mouw & M. S. Lawrence & G. Getz, 2018. "Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04002-4
    DOI: 10.1038/s41467-018-04002-4
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    Cited by:

    1. Gal Gilad & Mark D M Leiserson & Roded Sharan, 2021. "A data-driven approach for constructing mutation categories for mutational signature analysis," PLOS Computational Biology, Public Library of Science, vol. 17(10), pages 1-15, October.
    2. André Bortolini Silveira & Alexandre Houy & Olivier Ganier & Begüm Özemek & Sandra Vanhuele & Anne Vincent-Salomon & Nathalie Cassoux & Pascale Mariani & Gaelle Pierron & Serge Leyvraz & Damian Rieke , 2024. "Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Snaedis Kristmundsdottir & Hakon Jonsson & Marteinn T. Hardarson & Gunnar Palsson & Doruk Beyter & Hannes P. Eggertsson & Arnaldur Gylfason & Gardar Sveinbjornsson & Guillaume Holley & Olafur A. Stefa, 2023. "Sequence variants affecting the genome-wide rate of germline microsatellite mutations," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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