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

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.

SUBMITTER: Groschel S

PROVIDER: S-EPMC6456501 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Gröschel Stefan S Hübschmann Daniel D Raimondi Francesco F Horak Peter P Warsow Gregor G Fröhlich Martina M Klink Barbara B Gieldon Laura L Hutter Barbara B Kleinheinz Kortine K Bonekamp David D Marschal Oliver O Chudasama Priya P Mika Jagoda J Groth Marie M Uhrig Sebastian S Krämer Stephen S Heining Christoph C Heilig Christoph E CE Richter Daniela D Reisinger Eva E Pfütze Katrin K Eils Roland R Wolf Stephan S von Kalle Christof C Brandts Christian C Scholl Claudia C Weichert Wilko W Richter Stephan S Bauer Sebastian S Penzel Roland R Schröck Evelin E Stenzinger Albrecht A Schlenk Richard F RF Brors Benedikt B Russell Robert B RB Russell Robert B RB Glimm Hanno H Schlesner Matthias M Fröhling Stefan S

Nature communications 20190409 1

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 e ...[more]

PMID: 30967556

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Project description:HIPO project: HIPO_021 Importance: Chordomas are rare tumors of the axial skeleton and skull base with few therapeutic options and no clinically validated molecular drug targets. The value of comprehensive genomic analyses for guiding medical therapy of patients with advanced-stage chordoma is unknown.Objective: To identify therapeutically tractable genetic lesions in a cohort of chordoma patients within a genomics-guided precision oncology program and to document the outcome of individualized, molecularly targeted chordoma therapy.Design, Setting, and Participants: We performed whole-exome sequencing of tumor and matched germline control samples from seven patients with locally advanced or metastatic chordoma who were enrolled in a cross-institutional molecular stratification registry trial for younger adults with advanced-stage cancer across all histologies and patients with rare tumors. All patients were heavily pretreated and had progressive disease prior to molecular analysis.Interventions: Individualized medical therapy was administered according to the patients’ molecular profiles.Main Outcomes and Measures: Candidate therapeutic targets identified by whole-exome sequencing and response to genotype-directed therapy.Results: All patients harbored alterations of two or more genes known to be involved in DNA repair via homologous recombination (HR), including heterozygous deletions of ERCC6, FANC family members, RAD51L (n = 6), BRCA2 (n = 5), ATR, CHEK2, RAD18, RAD51B, and XRCC3 (n = 4); inactivating PTEN mutations coupled with loss of heterozygosity (n = 2); and pathogenic germline variants in BRCA2 (n = 1), NBN (n = 1), and CHEK2 (n = 1) that were accompanied by somatic deletion of the corresponding wild-type alleles. Consistently, a mutational signature associated with defective HR was enriched in all samples and co-occurred with extensive genomic instability, as evidenced by HR deficiency scores and high numbers of large-scale state transitions. These results prompted off-label treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib in a patient whose tumor was refractory to irradiation and systemic treatment with imatinib, which led to a prolonged response and substantial clinical improvement.Conclusions and Relevance: Advanced-stage chordomas are frequently characterized by genomic imprints of defective HR DNA repair. HR deficiency represents a new therapeutic opportunity in this intractable disease through repositioning of PARP inhibitors that warrants further exploration in clinical trials.

Dataset Information

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

Publications

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

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