1. Cell Biology
  2. Cancer Biology
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SPOP mutation leads to genomic instability in prostate cancer

  1. Gunther Boysen
  2. Christopher E Barbieri
  3. Davide Prandi
  4. Mirjam Blattner
  5. Sung-Suk Chae
  6. Arun Dahija
  7. Srilakshmi Nataraj
  8. Dennis Huang
  9. Clarisse Marotz
  10. Limei Xu
  11. Julie Huang
  12. Paola Lecca
  13. Sagar Chhangawala
  14. Deli Liu
  15. Pengbo Zhou
  16. Andrea Sboner
  17. Johann S de Bono
  18. Francesca Demichelis
  19. Yariv Houvras
  20. Mark A Rubin  Is a corresponding author
  1. Weill Cornell Medical College, United Kingdom
  2. Weill Cornell Medical College, United States
  3. University of Trento, Italy
  4. Institute of Cancer Research, United Kingdom
Research Article
  • Cited 85
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Cite this article as: eLife 2015;4:e09207 doi: 10.7554/eLife.09207

Abstract

Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer, modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA damaging therapeutics.

Article and author information

Author details

  1. Gunther Boysen

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United Kingdom
    Competing interests
    No competing interests declared.
  2. Christopher E Barbieri

    Department of Urologygy, Weill Cornell Medical College, New York, United States
    Competing interests
    Christopher E Barbieri, A patent (US Patent Application No: 2013/0331,279) has been issued to Weill Medical College of Cornell University on SPOP mutations in prostate cancer; is listed as co-inventor.
  3. Davide Prandi

    Centre for Integrative Biologygy, University of Trento, Trento, Italy
    Competing interests
    No competing interests declared.
  4. Mirjam Blattner

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  5. Sung-Suk Chae

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  6. Arun Dahija

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  7. Srilakshmi Nataraj

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  8. Dennis Huang

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  9. Clarisse Marotz

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  10. Limei Xu

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  11. Julie Huang

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  12. Paola Lecca

    Centre for Integrative Biologygy, University of Trento, Trento, Italy
    Competing interests
    No competing interests declared.
  13. Sagar Chhangawala

    Department of Surgery, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  14. Deli Liu

    Department of Urologygy, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  15. Pengbo Zhou

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  16. Andrea Sboner

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  17. Johann S de Bono

    Division of Clinical Studies, Institute of Cancer Research, London, United Kingdom
    Competing interests
    No competing interests declared.
  18. Francesca Demichelis

    Centre for Integrative Biologygy, University of Trento, Trento, Italy
    Competing interests
    No competing interests declared.
  19. Yariv Houvras

    Department of Surgery, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  20. Mark A Rubin

    Department of Pathologygy and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    For correspondence
    rubinma@med.cornell.edu
    Competing interests
    Mark A Rubin, A patent (US Patent Application No: 2013/0331,279) has been issued to Weill Medical College of Cornell University on SPOP mutations in prostate cancer; is listed as co-inventor.

Ethics

Animal experimentation: All protocols were performed with prior approval of the WCMC IACUC under protocol 2012-0065.

Reviewing Editor

  1. Joaquín M Espinosa, University of Colorado at Boulder, United States

Publication history

  1. Received: June 3, 2015
  2. Accepted: September 16, 2015
  3. Accepted Manuscript published: September 16, 2015 (version 1)
  4. Version of Record published: October 27, 2015 (version 2)

Copyright

© 2015, Boysen 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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