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Nat Commun. 2019 Apr 9;10(1):1635. doi: 10.1038/s41467-019-09633-9.

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

Gröschel S1,2,3, Hübschmann D4,5,6,7, Raimondi F8,9, Horak P10,11, Warsow G4,12, Fröhlich M10,13, Klink B14,15, Gieldon L14,15, Hutter B10,13, Kleinheinz K4,16, Bonekamp D17, Marschal O18, Chudasama P10,11, Mika J19,20, Groth M11,20, Uhrig S10,13,20, Krämer S4,20, Heining C15,21, Heilig CE11, Richter D15,21, Reisinger E4,12, Pfütze K10,22, Eils R10,4,22, Wolf S10,23, von Kalle C10,22,24, Brandts C25,26, Scholl C10,27, Weichert W28,29, Richter S15,30, Bauer S31,32, Penzel R10,33, Schröck E14,15, Stenzinger A10,33, Schlenk RF34,10,35,36, Brors B10,13, Russell RB8,9, Glimm H15,21, Schlesner M10,4,37, Fröhling S38,39,40.

Author information

1
Molecular Leukemogenesis Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. stefan.groeschel@dkfz-heidelberg.de.
2
Department of Internal Medicine V, Heidelberg University Hospital, 69120, Heidelberg, Germany. stefan.groeschel@dkfz-heidelberg.de.
3
German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. stefan.groeschel@dkfz-heidelberg.de.
4
Division of Theoretical Bioinformatics, DKFZ, 69120, Heidelberg, Germany.
5
Division of Stem Cells and Cancer, DKFZ, 69120, Heidelberg, Germany.
6
Heidelberg Institute for Stem Cell Technology and Experimental Medicine, 69120, Heidelberg, Germany.
7
Department of Pediatric Immunology, Hematology and Oncology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
8
BioQuant, Heidelberg University, 69120, Heidelberg, Germany.
9
Heidelberg University Biochemistry Center, 69120, Heidelberg, Germany.
10
German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
11
Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, 69120, Heidelberg, Germany.
12
Omics IT and Data Management Core Facility, DKFZ, 69120, Heidelberg, Germany.
13
Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, 69120, Heidelberg, Germany.
14
Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany.
15
DKTK, 01307, Dresden, Germany.
16
Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, 69120, Heidelberg, Germany.
17
Division of Radiology, DKFZ, 69120, Heidelberg, Germany.
18
Onkologische Schwerpunktpraxis, 38100, Braunschweig, Germany.
19
Molecular Leukemogenesis Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
20
Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany.
21
Department of Translational Medical Oncology, NCT Dresden and University Hospital Carl Gustav Carus, 01307 Dresden, and DKFZ, 69120, Heidelberg, Germany.
22
DKFZ-Heidelberg Center for Personalized Oncology (HIPO), 69120, Heidelberg, Germany.
23
Genomics and Proteomics Core Facility, DKFZ, 69120, Heidelberg, Germany.
24
Division of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, 69120, Heidelberg, Germany.
25
University Cancer Center Frankfurt (UCT), Department of Medicine, Hematology/Oncology, Goethe University, 60595, Frankfurt, Germany.
26
DKTK, 60595, Frankfurt, Germany.
27
Division of Applied Functional Genomics, DKFZ, 69120, Heidelberg, Germany.
28
Institute of Pathology, Technical University Munich, 81675, Munich, Germany.
29
DKTK, 81675, Munich, Germany.
30
Department of Internal Medicine I, University Hospital Carl Gustav Carus, 01307, Dresden, Germany.
31
West German Cancer Center, University of Duisburg-Essen, 45147, Essen, Germany.
32
DKTK, 45147, Essen, Germany.
33
Institute of Pathology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
34
Department of Internal Medicine V, Heidelberg University Hospital, 69120, Heidelberg, Germany.
35
Department of Internal Medicine VI, Heidelberg University Hospital, 69120, Heidelberg, Germany.
36
NCT Trial Center, NCT Heidelberg and DKFZ, 69120, Heidelberg, Germany.
37
Bioinformatics and Omics Data Analytics Group, DKFZ, 69120, Heidelberg, Germany.
38
German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.
39
Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, 69120, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.
40
DKFZ-Heidelberg Center for Personalized Oncology (HIPO), 69120, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.

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.

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