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Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers

Author

Listed:
  • Wataru Sakai

    (Division of Human Biology,
    Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA)

  • Elizabeth M. Swisher

    (Department of Obstetrics and Gynecology,
    University of Washington, Seattle, Washington 98195-7720, USA)

  • Beth Y. Karlan

    (Cedars-Sinai Medical Center, Women’s Cancer Research Institute, Los Angeles, California 90048-1865, USA)

  • Mukesh K. Agarwal

    (Mayo Clinic, Rochester, Minnesota 55905, USA)

  • Jake Higgins

    (University of Washington, Seattle, Washington 98195-7720, USA
    University of Washington, Seattle, Washington 98195-7720, USA)

  • Cynthia Friedman

    (Division of Human Biology,)

  • Emily Villegas

    (Division of Human Biology,
    Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA)

  • Céline Jacquemont

    (Division of Human Biology,
    Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA)

  • Daniel J. Farrugia

    (Mayo Clinic, Rochester, Minnesota 55905, USA)

  • Fergus J. Couch

    (Mayo Clinic, Rochester, Minnesota 55905, USA)

  • Nicole Urban

    (Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA)

  • Toshiyasu Taniguchi

    (Division of Human Biology,
    Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA)

Abstract

Resistance in BRCA2 cancers The platinum chemotherapeutics such as cisplatin and carboplatin are in clinical use in patients with BRCA2-mutated ovarian cancer. The initial response is generally good but most ovarian carcinomas ultimately become resistant to therapy. Two papers in this issue have identified a possible cause of this resistance as further mutation of the BRCA2 gene. Mutations in BRCA2 are associated with familial breast and ovarian cancer. Loss of BRCA2 function impairs DNA repair by homologous recombination and renders cells particular sensitive to cisplatin and also to PARP (poly (ADP-ribose) polymerase) inhibitors. The secondary 'resistance' mutations act by restoring the wild-type BRCA2 reading frame.

Suggested Citation

  • Wataru Sakai & Elizabeth M. Swisher & Beth Y. Karlan & Mukesh K. Agarwal & Jake Higgins & Cynthia Friedman & Emily Villegas & Céline Jacquemont & Daniel J. Farrugia & Fergus J. Couch & Nicole Urban & , 2008. "Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers," Nature, Nature, vol. 451(7182), pages 1116-1120, February.
    • Handle: RePEc:nat:nature:v:451:y:2008:i:7182:d:10.1038_nature06633
    DOI: 10.1038/nature06633
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    Cited by:

    1. Fumiaki Ito & Ziyuan Li & Leonid Minakhin & Gurushankar Chandramouly & Mrityunjay Tyagi & Robert Betsch & John J. Krais & Bernadette Taberi & Umeshkumar Vekariya & Marissa Calbert & Tomasz Skorski & N, 2024. "Structural basis for a Polθ helicase small-molecule inhibitor revealed by cryo-EM," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Yuxin Huang & Wenjing Li & Tzeh Foo & Jae-Hoon Ji & Bo Wu & Nozomi Tomimatsu & Qingming Fang & Boya Gao & Melissa Long & Jingfei Xu & Rouf Maqbool & Bipasha Mukherjee & Tengyang Ni & Salvador Alejo & , 2024. "DSS1 restrains BRCA2’s engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Georgia Zoumpoulidou & Carlos Alvarez-Mendoza & Caterina Mancusi & Ritika-Mahmuda Ahmed & Milly Denman & Christopher D. Steele & Maxime Tarabichi & Errin Roy & Lauren R. Davies & Jiten Manji & Camilla, 2021. "Therapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Jennifer B. Shah & Dana Pueschl & Bradley Wubbenhorst & Mengyao Fan & John Pluta & Kurt D’Andrea & Anna P. Hubert & Jake S. Shilan & Wenting Zhou & Adam A. Kraya & Alba Llop Guevara & Catherine Ruan &, 2022. "Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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