Defective homologous recombination DNA repair as therapeutic target in advanced chordoma. View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

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 von 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, Stefan Fröhling

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. More... »

PAGES

1635

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41467-019-09633-9

DOI

http://dx.doi.org/10.1038/s41467-019-09633-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1113327777

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30967556


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456 schema:name DKTK, 81675, Munich, Germany.
457 Institute of Pathology, Technical University Munich, 81675, Munich, Germany.
458 rdf:type schema:Organization
459 https://www.grid.ac/institutes/grid.7497.d schema:alternateName German Cancer Research Center
460 schema:name Bioinformatics and Omics Data Analytics Group, DKFZ, 69120, Heidelberg, Germany.
461 DKFZ-Heidelberg Center for Personalized Oncology (HIPO), 69120, Heidelberg, Germany.
462 DKFZ-Heidelberg Center for Personalized Oncology (HIPO), 69120, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.
463 DKTK, 01307, Dresden, Germany.
464 DKTK, 60595, Frankfurt, Germany.
465 Department of Internal Medicine V, Heidelberg University Hospital, 69120, Heidelberg, Germany. stefan.groeschel@dkfz-heidelberg.de.
466 Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, 69120, Heidelberg, Germany.
467 Division of Applied Functional Genomics, DKFZ, 69120, Heidelberg, Germany.
468 Division of Radiology, DKFZ, 69120, Heidelberg, Germany.
469 Division of Theoretical Bioinformatics, DKFZ, 69120, Heidelberg, Germany.
470 Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, 69120, Heidelberg, Germany.
471 Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, 69120, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.
472 Division of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, 69120, Heidelberg, Germany.
473 Genomics and Proteomics Core Facility, DKFZ, 69120, Heidelberg, Germany.
474 German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
475 German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.
476 German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. stefan.groeschel@dkfz-heidelberg.de.
477 Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany.
478 Institute of Pathology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
479 Molecular Leukemogenesis Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. stefan.groeschel@dkfz-heidelberg.de.
480 Omics IT and Data Management Core Facility, DKFZ, 69120, Heidelberg, Germany.
481 University Cancer Center Frankfurt (UCT), Department of Medicine, Hematology/Oncology, Goethe University, 60595, Frankfurt, Germany.
482 rdf:type schema:Organization
483 https://www.grid.ac/institutes/grid.7700.0 schema:alternateName Heidelberg University
484 schema:name BioQuant, Heidelberg University, 69120, Heidelberg, Germany.
485 Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, 69120, Heidelberg, Germany.
486 Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, 69120, Heidelberg, Germany.
487 Division of Theoretical Bioinformatics, DKFZ, 69120, Heidelberg, Germany.
488 Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, 69120, Heidelberg, Germany.
489 Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany.
490 German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
491 Heidelberg University Biochemistry Center, 69120, Heidelberg, Germany.
492 Molecular Leukemogenesis Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
493 rdf:type schema:Organization
 




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