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Published on: August 25, 2023
Genomic Characterization of Chondrosarcoma Reveals Potential Therapeutic Targets
Michael J Wagner1,2,3, Erica M Pimenta1, Nathan W Sweeney4
1Sarcoma and Bone Cancer Center, Dana-Farber Cancer Institute, Boston, MA.
Purpose:
Chondrosarcomas are rare cancers of cartilage with limited systemic therapy options. To identify potential therapeutic targets, this study investigated the molecular and immune landscape of three chondrosarcoma subtypes using a large database of clinical-grade sequencing results.
Methods:
Deidentified records from patients with a histologic diagnosis of conventional, dedifferentiated, or mesenchymal chondrosarcoma sequenced by the Tempus xT DNA assay were included. Microsatellite instability (MSI) and tumor mutational burden (TMB) were determined from sequencing data. The expression of PD-L1 and mismatch repair enzymes was evaluated in cases with available immunohistochemistry (IHC) data.
Results:
Of the 149 patients, 103 had conventional chondrosarcoma, 31 dedifferentiated chondrosarcoma, and 15 mesenchymal chondrosarcoma. Across the cohort, 44% (n = 65) had an IDH1 or IDH2 mutation. No cases were MSI high. One conventional chondrosarcoma patient had a TMB >10 mut/Mb. Among 112 patients with available PD-L1 IHC, 10% of conventional (n = 7), 45% of dedifferentiated (n = 13), and 17% of mesenchymal cases (n = 2) were PD-L1-positive. The most common somatic alterations were in IDH1 (34%) and TP53 (28%) in conventional chondrosarcoma; TP53 (68%), TERT (65%), IDH1 (39%), IDH2 (39%), CDKN2A (35%), and CDKN2B (35%) in dedifferentiated chondrosarcoma; and HEY1-NCOA2 fusions (87%) and CDKN2A (20%) in mesenchymal chondrosarcoma. MTAP was deleted in >10% of each subtype, and potentially actionable PDGFRB mutations were identified in 13% of dedifferentiated chondrosarcomas.
Conclusion:
These findings reinforce therapeutic efforts to target IDH signaling in chondrosarcoma, provide insight into varied subpopulation response to immune checkpoint inhibitors, and identify new potential therapeutic targets for clinical development in chondrosarcoma.
Insights
This study analyzed chondrosarcoma subtypes, finding IDH mutations in 44% and varied PD-L1 expression. Findings support targeting IDH signaling and identify new therapeutic avenues for rare cartilage cancers.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Chondrosarcomas are rare bone cancers with limited treatment options.
- Understanding their molecular and immune profiles is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the molecular and immune landscape of conventional, dedifferentiated, and mesenchymal chondrosarcoma subtypes.
- To identify potential therapeutic targets for chondrosarcoma treatment.
Main Methods:
- Analysis of clinical-grade sequencing data from 149 chondrosarcoma patients.
- Determination of microsatellite instability (MSI), tumor mutational burden (TMB), and PD-L1 expression via immunohistochemistry (IHC).
- Evaluation of somatic alterations including IDH1/2 mutations and gene fusions.
Main Results:
- 44% of patients had IDH1 or IDH2 mutations; no cases were MSI high.
- PD-L1 positivity varied by subtype: 10% conventional, 45% dedifferentiated, 17% mesenchymal.
- Common alterations included IDH1/TP53 in conventional, TP53/TERT/IDH1/IDH2 in dedifferentiated, and HEY1-NCOA2 fusions in mesenchymal chondrosarcoma.
Conclusions:
- Findings support targeting IDH signaling in chondrosarcoma.
- Insights into immune checkpoint inhibitor response in different chondrosarcoma subtypes.
- Identification of novel therapeutic targets, including PDGFRB mutations, for clinical development.
