IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-04002-4.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-04002-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-018-04002-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04002-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.