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. 2025 Aug 15;131(16):e70033.
doi: 10.1002/cncr.70033.

Mutational analysis of primary and advanced chordoma tissue using next-generation sequencing

Josh Chan  1 , Joseph K Kendal  1   2 , Zhenfeng Duan  3 , Al Ferreira  3 , Alireza Samiei  2 , Scott D Nelson  2 , Arun Singh  2 , Elizabeth L Lord  2 , Brooke Crawford  3 , Nicholas M Bernthal  2 , Francis J Hornicek  3
Affiliations

Mutational analysis of primary and advanced chordoma tissue using next-generation sequencing

Josh Chan et al. Cancer. .

Abstract

Background: Chordomas are rare ectodermal bone malignancies derived from transformed notochordal remnants. Histologic variants include conventional (80%-90%), chondroid (5%-15%), and dedifferentiated (2%-8%). Because chordomas are relatively resistant to chemotherapy and radiotherapy, novel targeted agents are needed to expand treatment approaches and improve outcomes. This study analyzes the genomic landscape of chordoma and identifies potential pathogenic and druggable targets.

Methods: Eighty-six tumor samples derived from chordoma patients treated at Massachusetts General Hospital, University of California, Los Angeles, and the University of Miami were included. Tumor specimens were sent for comprehensive molecular profiling using next-generation sequencing. The most frequently mutated genes were identified and categorized by subtype, and microsatellite instability and programmed death ligand-1 (PD-L1) staining were assessed.

Results: Histologic subtypes included 70 conventional (81.4%), nine chondroid (10.5%), and seven dedifferentiated chordomas (8.1%). The most common mutations were cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) (28 of 86, 33%), low-density lipoprotein receptor-related protein 1B (10 of 86, 12%), polybromo-1 (9 of 86, 11%), and epidermal growth factor receptor (EGFR) (8 of 86, 9%). By subtype, CDKN2A/B mutation was most common in conventional chordoma (24 of 70, 34%), and chondroid chordoma (3 of 9, 33%). CDKN2A/B and EGFR mutations were most common in dedifferentiated chordoma (2/7, 29%). Microsatellite instability was not detected in seven of 69 (10.1%) samples. PD-L1 staining of tumor and immune cells was scarce, with scores <1 in 38 of 41 (92.7%) and 22 of 25 (88%) patients, respectively.

Conclusions: This study provides a robust, high-dimensional sequencing assessment from 86 chordoma tissue samples and a descriptive overview of the genomic landscape of this rare, difficult to treat malignancy. Future studies should include in vitro assessment of gain and loss of function of frequently altered pathways to validate these findings.

Keywords: CDKN2A/B; PD‐L1; chordoma; molecular profiling; mutational analysis; next‐generation sequencing.

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Conflict of interest statement

Brooke Crawford reports consulting fees from Zimmer Biomet Holdings, Inc; and fees for professional activities from IlluminOss Medical, Inc. Elizabeth L. Lord reports consulting fees from Globus Medical, Inc and SI‐BONE, Inc. Arun Singh reports consulting fees from Deciphera Pharmaceuticals Inc. The other authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Disease progression from all samples and those with cyclin‐dependent kinase inhibitor 2A/B mutations.
FIGURE 2
FIGURE 2
Microsatellite instability data derived from 69 patients: 58 stable (84.1%), seven not detected (10.1%), three undetermined (4.3%), and one high (1.4%).
FIGURE 3
FIGURE 3
Outcome data derived from 32 patients: 15 alive with disease (46.9%), 15 died of disease (46.9%), one alive without disease (3.1%), and one alive awaiting surgery (3.1%).
FIGURE 4
FIGURE 4
Workflow for chordoma tissue analysis.
See this image and copyright information in PMC

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