1. Genetics and Genomics
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Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks

  1. Hui Zhao
  2. Bernard Thienpont
  3. Betül T Yesilyurt
  4. Matthieu Moisse
  5. Joke Reumers
  6. Lieve Coenegrachts
  7. Xavier Sagaert
  8. Stefanie Schrauwen
  9. Dominiek Smeets
  10. Gert Matthijs
  11. Stein Aerts
  12. Jan Cools
  13. Alex Metcalf
  14. Amanda Spurdle
  15. ANECS
  16. Frederic Amant
  17. Diether Lambrechts  Is a corresponding author
  1. VIB Vesalius Research Center, KU Leuven, Belgium
  2. University Hospital Gasthuisberg, Belgium
  3. KU Leuven, Belgium
  4. University of Leuven, Belgium
  5. Queensland Institute of Medical Research, Australia
  6. PO Royal Brisbane Hospital, Australia
Research Article
  • Cited 43
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Cite this article as: eLife 2014;3:e02725 doi: 10.7554/eLife.02725

Abstract

DNA replication errors that persist as mismatch mutations make up the molecular fingerprint of mismatch repair (MMR)-deficient tumors and convey them with resistance to standard therapy. Using whole-genome and -exome sequencing, we here confirm an MMR-deficient mutation signature that is distinct from other tumor genomes, but surprisingly similar to germ-line DNA, confirming that a substantial fraction of human genetic variation arises through mutations escaping MMR. Moreover, we identify a large set of recurrent indels that may serve to detect microsatellite instability (MSI). Indeed, using endometrial tumors with immunohistochemically-proven MMR deficiency, we optimize a novel marker set capable of detecting MSI and show it to have greater specificity and selectivity than standard MSI tests. Additionally, we show that recurrent indels are enriched for the 'DNA double-strand break repair by homologous recombination' pathway. Consequently, DSB repair is reduced in MMR-deficient tumors, triggering a dose-dependent sensitivity of MMR-deficient tumor cultures to DSB inducers.

Article and author information

Author details

  1. Hui Zhao

    VIB Vesalius Research Center, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  2. Bernard Thienpont

    VIB Vesalius Research Center, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  3. Betül T Yesilyurt

    VIB Vesalius Research Center, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  4. Matthieu Moisse

    VIB Vesalius Research Center, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  5. Joke Reumers

    VIB Vesalius Research Center, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  6. Lieve Coenegrachts

    University Hospital Gasthuisberg, Leuven, Belgium
    Competing interests
    No competing interests declared.
  7. Xavier Sagaert

    University Hospital Gasthuisberg, Leuven, Belgium
    Competing interests
    No competing interests declared.
  8. Stefanie Schrauwen

    University Hospital Gasthuisberg, Leuven, Belgium
    Competing interests
    No competing interests declared.
  9. Dominiek Smeets

    VIB Vesalius Research Center, KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  10. Gert Matthijs

    KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  11. Stein Aerts

    University of Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  12. Jan Cools

    KU Leuven, Leuven, Belgium
    Competing interests
    No competing interests declared.
  13. Alex Metcalf

    Queensland Institute of Medical Research, Brisbane, Australia
    Competing interests
    No competing interests declared.
  14. Amanda Spurdle

    Queensland Institute of Medical Research, Brisbane, Australia
    Competing interests
    No competing interests declared.
  15. ANECS

    PO Royal Brisbane Hospital, Brisbane, Australia
    Competing interests
    No competing interests declared.
  16. Frederic Amant

    University Hospital Gasthuisberg, Leuven, Belgium
    Competing interests
    No competing interests declared.
  17. Diether Lambrechts

    VIB Vesalius Research Center, KU Leuven, Leuven, Belgium
    For correspondence
    diether.lambrechts@vib-kuleuven.be
    Competing interests
    Diether Lambrechts, an inventor on a patent application regarding the use of recurrent indels to detect MSI. The VIB is owner of this patent application, and the said patent application has been licensed to an outside company. Neither VIB nor any of the authors have equity stakes in the company. However, VIB stands to eventually receive royalties.

Ethics

Human subjects: Informed consent and consent to publish was obtained from all patients. Ethical approval was obtained at the ethical committee of University Hospital Gasthuisberg of Leuven with identifier ML2266.

Reviewing Editor

  1. John Stamatoyannopoulos, University of Washington, United States

Publication history

  1. Received: March 8, 2014
  2. Accepted: July 30, 2014
  3. Accepted Manuscript published: August 1, 2014 (version 1)
  4. Version of Record published: August 22, 2014 (version 2)

Copyright

© 2014, Zhao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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