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Updated: Sep 11, 2025
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Mutational analysis of primary and advanced chordoma tissue using next-generation sequencing
Josh Chan1, Joseph K Kendal1,2, Zhenfeng Duan3
1Department of Surgery, Section of Orthopaedic Surgery, University of Calgary, Calgary, Alberta, Canada.
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.
Insights
This study reveals common genetic mutations in chordoma, a rare bone cancer. Identifying these genomic alterations, such as CDKN2A/B and EGFR, offers potential targets for new therapies against this difficult-to-treat disease.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Chordomas are rare bone cancers originating from notochordal remnants.
- Histologic subtypes include conventional, chondroid, and dedifferentiated chordomas.
- Current treatments face challenges due to resistance to chemotherapy and radiotherapy.
Purpose of the Study:
- To analyze the genomic landscape of chordoma.
- To identify potential pathogenic and druggable targets for novel therapies.
- To understand the genetic alterations across different chordoma subtypes.
Main Methods:
- Comprehensive molecular profiling using next-generation sequencing on 86 chordoma tumor samples.
- Identification and categorization of frequently mutated genes by histologic subtype.
- Assessment of microsatellite instability and programmed death ligand-1 (PD-L1) expression.
Main Results:
- Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) was the most common mutation (33%), followed by low-density lipoprotein receptor-related protein 1B (12%) and epidermal growth factor receptor (EGFR) (9%).
- CDKN2A/B mutations were prevalent in conventional (34%) and chondroid (33%) chordomas.
- Dedifferentiated chordomas showed high rates of CDKN2A/B and EGFR mutations (29%).
- Microsatellite instability was infrequent, and PD-L1 expression was scarce.
Conclusions:
- This study provides a detailed genomic overview of 86 chordoma samples.
- Identified frequent mutations in CDKN2A/B and EGFR present potential therapeutic targets.
- Further in vitro studies are needed to validate the functional impact of these alterations.
