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Defective homologous recombination DNA repair as therapeutic target in advanced chordoma

Author

Listed:
  • Stefan Gröschel

    (German Cancer Research Center (DKFZ)
    Heidelberg University Hospital
    German Cancer Consortium (DKTK))

  • Daniel Hübschmann

    (DKFZ
    DKFZ
    Heidelberg Institute for Stem Cell Technology and Experimental Medicine
    Heidelberg University Hospital)

  • Francesco Raimondi

    (Heidelberg University
    Heidelberg University Biochemistry Center)

  • Peter Horak

    (German Cancer Consortium (DKTK)
    National Center for Tumor Diseases (NCT) Heidelberg and DKFZ)

  • Gregor Warsow

    (DKFZ
    DKFZ)

  • Martina Fröhlich

    (German Cancer Consortium (DKTK)
    DKFZ and NCT Heidelberg)

  • Barbara Klink

    (Technische Universität Dresden
    DKTK)

  • Laura Gieldon

    (Technische Universität Dresden
    DKTK)

  • Barbara Hutter

    (German Cancer Consortium (DKTK)
    DKFZ and NCT Heidelberg)

  • Kortine Kleinheinz

    (DKFZ
    Heidelberg University)

  • David Bonekamp

    (DKFZ)

  • Oliver Marschal

    (Onkologische Schwerpunktpraxis)

  • Priya Chudasama

    (German Cancer Consortium (DKTK)
    National Center for Tumor Diseases (NCT) Heidelberg and DKFZ)

  • Jagoda Mika

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Marie Groth

    (National Center for Tumor Diseases (NCT) Heidelberg and DKFZ
    Heidelberg University)

  • Sebastian Uhrig

    (German Cancer Consortium (DKTK)
    DKFZ and NCT Heidelberg
    Heidelberg University)

  • Stephen Krämer

    (DKFZ
    Heidelberg University)

  • Christoph Heining

    (DKTK
    NCT Dresden and University Hospital Carl Gustav Carus)

  • Christoph E. Heilig

    (National Center for Tumor Diseases (NCT) Heidelberg and DKFZ)

  • Daniela Richter

    (DKTK
    NCT Dresden and University Hospital Carl Gustav Carus)

  • Eva Reisinger

    (DKFZ
    DKFZ)

  • Katrin Pfütze

    (German Cancer Consortium (DKTK)
    DKFZ-Heidelberg Center for Personalized Oncology (HIPO))

  • Roland Eils

    (German Cancer Consortium (DKTK)
    DKFZ
    DKFZ-Heidelberg Center for Personalized Oncology (HIPO))

  • Stephan Wolf

    (German Cancer Consortium (DKTK)
    DKFZ)

  • Christof Kalle

    (German Cancer Consortium (DKTK)
    DKFZ-Heidelberg Center for Personalized Oncology (HIPO)
    National Center for Tumor Diseases (NCT) Heidelberg and DKFZ)

  • Christian Brandts

    (Goethe University
    DKTK)

  • Claudia Scholl

    (German Cancer Consortium (DKTK)
    DKFZ)

  • Wilko Weichert

    (Technical University Munich
    DKTK)

  • Stephan Richter

    (DKTK
    University Hospital Carl Gustav Carus)

  • Sebastian Bauer

    (University of Duisburg-Essen
    DKTK)

  • Roland Penzel

    (German Cancer Consortium (DKTK)
    Heidelberg University Hospital)

  • Evelin Schröck

    (Technische Universität Dresden
    DKTK)

  • Albrecht Stenzinger

    (German Cancer Consortium (DKTK)
    Heidelberg University Hospital)

  • Richard F. Schlenk

    (Heidelberg University Hospital
    German Cancer Consortium (DKTK)
    Heidelberg University Hospital
    NCT Heidelberg and DKFZ)

  • Benedikt Brors

    (German Cancer Consortium (DKTK)
    DKFZ and NCT Heidelberg)

  • Robert B. Russell

    (Heidelberg University
    Heidelberg University Biochemistry Center)

  • Hanno Glimm

    (DKTK
    NCT Dresden and University Hospital Carl Gustav Carus)

  • Matthias Schlesner

    (German Cancer Consortium (DKTK)
    DKFZ
    DKFZ)

  • Stefan Fröhling

    (German Cancer Consortium (DKTK)
    National Center for Tumor Diseases (NCT) Heidelberg and DKFZ
    DKFZ-Heidelberg Center for Personalized Oncology (HIPO))

Abstract

Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.

Suggested Citation

  • Stefan Gröschel & Daniel Hübschmann & Francesco Raimondi & Peter Horak & Gregor Warsow & Martina Fröhlich & Barbara Klink & Laura Gieldon & Barbara Hutter & Kortine Kleinheinz & David Bonekamp & Olive, 2019. "Defective homologous recombination DNA repair as therapeutic target in advanced chordoma," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09633-9
    DOI: 10.1038/s41467-019-09633-9
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    Cited by:

    1. Mrinal M. Gounder & Narasimhan P. Agaram & Sally E. Trabucco & Victoria Robinson & Richard A. Ferraro & Sherri Z. Millis & Anita Krishnan & Jessica Lee & Steven Attia & Wassim Abida & Alexander Drilon, 2022. "Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Tanaz Sharifnia & Mathias J. Wawer & Amy Goodale & Yenarae Lee & Mariya Kazachkova & Joshua M. Dempster & Sandrine Muller & Joan Levy & Daniel M. Freed & Josh Sommer & Jérémie Kalfon & Francisca Vazqu, 2023. "Mapping the landscape of genetic dependencies in chordoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Qilin Zhang & Ziyan Xu & Rui Han & Yunzhi Wang & Zhen Ye & Jiajun Zhu & Yixin Cai & Fan Zhang & Jiangyan Zhao & Boyuan Yao & Zhaoyu Qin & Nidan Qiao & Ruofan Huang & Jinwen Feng & Yongfei Wang & Wenti, 2024. "Proteogenomic characterization of skull-base chordoma," Nature Communications, Nature, vol. 15(1), pages 1-32, December.

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