Defective homologous recombination DNA repair as therapeutic target in advanced chordoma

Stefan Gröschel (), Daniel Hübschmann, Francesco Raimondi, Peter Horak, Gregor Warsow, Martina Fröhlich, Barbara Klink, Laura Gieldon, Barbara Hutter, Kortine Kleinheinz, David Bonekamp, Oliver Marschal, Priya Chudasama, Jagoda Mika, Marie Groth, Sebastian Uhrig, Stephen Krämer, Christoph Heining, Christoph E. Heilig, Daniela Richter, Eva Reisinger, Katrin Pfütze, Roland Eils, Stephan Wolf, Christof Kalle, Christian Brandts, Claudia Scholl, Wilko Weichert, Stephan Richter, Sebastian Bauer, Roland Penzel, Evelin Schröck, Albrecht Stenzinger, Richard F. Schlenk, Benedikt Brors, Robert B. Russell, Hanno Glimm, Matthias Schlesner and Stefan Fröhling ()
Additional contact information
Stefan Gröschel: German Cancer Research Center (DKFZ)
Daniel Hübschmann: DKFZ
Francesco Raimondi: Heidelberg University
Peter Horak: German Cancer Consortium (DKTK)
Gregor Warsow: DKFZ
Martina Fröhlich: German Cancer Consortium (DKTK)
Barbara Klink: Technische Universität Dresden
Laura Gieldon: Technische Universität Dresden
Barbara Hutter: German Cancer Consortium (DKTK)
Kortine Kleinheinz: DKFZ
David Bonekamp: DKFZ
Oliver Marschal: Onkologische Schwerpunktpraxis
Priya Chudasama: German Cancer Consortium (DKTK)
Jagoda Mika: German Cancer Research Center (DKFZ)
Marie Groth: National Center for Tumor Diseases (NCT) Heidelberg and DKFZ
Sebastian Uhrig: German Cancer Consortium (DKTK)
Stephen Krämer: DKFZ
Christoph Heining: DKTK
Christoph E. Heilig: National Center for Tumor Diseases (NCT) Heidelberg and DKFZ
Daniela Richter: DKTK
Eva Reisinger: DKFZ
Katrin Pfütze: German Cancer Consortium (DKTK)
Roland Eils: German Cancer Consortium (DKTK)
Stephan Wolf: German Cancer Consortium (DKTK)
Christof Kalle: German Cancer Consortium (DKTK)
Christian Brandts: Goethe University
Claudia Scholl: German Cancer Consortium (DKTK)
Wilko Weichert: Technical University Munich
Stephan Richter: DKTK
Sebastian Bauer: University of Duisburg-Essen
Roland Penzel: German Cancer Consortium (DKTK)
Evelin Schröck: Technische Universität Dresden
Albrecht Stenzinger: German Cancer Consortium (DKTK)
Richard F. Schlenk: Heidelberg University Hospital
Benedikt Brors: German Cancer Consortium (DKTK)
Robert B. Russell: Heidelberg University
Hanno Glimm: DKTK
Matthias Schlesner: German Cancer Consortium (DKTK)
Stefan Fröhling: German Cancer Consortium (DKTK)

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09633-9

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