Journal Article

DKFZ-2019-01097

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Defective homologous recombination DNA repair as therapeutic target in advanced chordoma.

Gröschel, S. (First author)DKFZ* ; Hübschmann, D. (First author)DKFZ* ; Raimondi, F. ; Horak, P.DKFZ* ; Warsow, G.DKFZ* ; Fröhlich, M.DKFZ* ; Klink, B. ; Gieldon, L.DKFZ* ; Hutter, B.DKFZ* ; Kleinheinz, K.DKFZ* ; Bonekamp, D.DKFZ* ; Marschal, O. ; Chudasama, P.DKFZ* ; Mika, J.DKFZ* ; Groth, M. ; Uhrig, S.DKFZ* ; Krämer, S.DKFZ* ; Heining, C.Extern* ; Heilig, C.DKFZ* ; Richter, D.DKFZ* ; Reisinger, E.DKFZ* ; Pfütze, K.DKFZ* ; Eils, R.DKFZ* ; Wolf, S.DKFZ* ; von Kalle, C.DKFZ* ; Brandts, C.DKFZ* ; Scholl, C.DKFZ* ; Weichert, W.DKFZ* ; Richter, S. ; Bauer, S.DKFZ* ; Penzel, R.DKFZ* ; Schröck, E.DKFZ* ; Stenzinger, A.DKFZ* ; Schlenk, R.DKFZ* ; Brors, B.DKFZ* ; Russell, R. B. ; Glimm, H. (Last author)DKFZ* ; Schlesner, M. (Last author)DKFZ* ; Fröhling, S. (Last author)DKFZ*

2019
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-019-09633-9

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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Contributing Institute(s):

1. NWG Molekulare Leukämogenese (A380)
2. DKTK Heidelberg (L101)
3. Theoretische Bioinformatik (B080)
4. A010 Stammzellen und Krebs (A010)
5. Translationale Medizinische Onkologie (B340)
6. Bioinformatik und Omics Data Analytics (B240)
7. Angewandte Bioinformatik (B330)
8. E010 Radiologie (E010)
9. KKE Mol. Hämatologie/Onkologie (A360)
10. Hochdurchsatz-Sequenzierung (W190)
11. Angewandte Funktionelle Genomik (B290)
12. DKTK Dresden (L301)
13. DKTK Frankfurt (L501)
14. DKTK München (L701)
15. DKTK Essen (L401)

Research Program(s):

1. 311 - Signalling pathways, cell and tumor biology (POF3-311) (POF3-311)

Appears in the scientific report 2019

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Database coverage:
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