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.
Highlights
Chordomas are rare bone tumors with few therapeutic options
A survey of single-nucleotide variants (SNVs), small insertions/deletions, structural rearrangements, and copy number changes using a combination of whole-exome sequencing (WES), whole-genome-sequencing (WGS), and targeted sequencing identified recurrent alterations in additional loci not previously implicated in chordoma, such as ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, and LYST, whose protein product regulates lysosomal trafficking[10]
These results prompted experimental treatment with a poly (ADP-ribose) polymerase (PARP) inhibitor in a patient whose tumor was refractory to irradiation and medical therapy, which led to a prolonged response and enabled the discovery of mutational destabilization of the autoinhibitory PARP1 alpha-helical domain (HD) as an yet unrecognized mechanism underlying acquired poly(ADP-ribose) polymerase (PARP) inhibitor resistance
Summary
Chordomas are rare bone tumors with few therapeutic options. Here we show, using wholeexome 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. 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. We observed that advanced chordomas may frequently harbor molecular alterations associated with impaired DNA repair via homologous recombination (HR) as potentially actionable genetic vulnerabilities These results prompted experimental treatment with a poly (ADP-ribose) polymerase (PARP) inhibitor in a patient whose tumor was refractory to irradiation and medical therapy, which led to a prolonged response and enabled the discovery of mutational destabilization of the autoinhibitory PARP1 alpha-helical domain (HD) as an yet unrecognized mechanism underlying acquired PARP inhibitor resistance
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