Related Experiment Video
Updated: Aug 9, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Methylthioadenosine phosphorylase gene deletions are frequently detected by fluorescence in situ hybridization in
Warren A Chow1, Victoria Bedell, Popsie Gaytan
1Department of Medical Oncology and Therapeutics Research, City of Hope Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA. wchow@coh.org
Abstract:
Chondrosarcomas are the second most common primary malignant tumor of bone. Chemotherapy for conventional chondrosarcomas is generally ineffective. Methylthioadenosine phosphorylase (MTAP) is a ubiquitous enzyme, essential in the salvage pathway of adenine and in methionine synthesis. MTAP-deficient cells are more susceptible than wild-type cells to pharmacologic inhibitors of de novo purine synthesis. Homozygous deletions of MTAP have been reported in hematologic and solid tumor malignancies. Based on these observations, we investigated the frequency of MTAP deletions in conventional, grade II chondrosarcomas by fluorescence in situ hybridization (FISH) analysis: 23 conventional, grade II chondrosarcoma patient samples from the Cleveland Clinic Foundation were analyzed for MTAP deletions. Nuclei were successfully extracted from 14 of 23 samples (61% evaluable) for FISH analysis: 7 of 14 samples (50%) showed either homozygous or hemizygous deletion of the MTAP gene, 6 of 14 (43%) failed to show deletion, and 1 of 14 (7%) was inconclusive. These findings suggest that approximately one-half of conventional, grade II chondrosarcomas may be preferentially sensitive to pharmacologic inhibitors of de novo purine synthesis. The present study led to development by the Intergroup Coalition Against Sarcomas of a phase II trial of pemetrexed, a multitargeted anti-folate, for advanced chondrosarcomas.
Insights
Approximately half of conventional grade II chondrosarcomas show deletions in the Methylthioadenosine phosphorylase (MTAP) gene. This suggests potential sensitivity to de novo purine synthesis inhibitors for these bone tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chondrosarcomas are the second most common primary bone malignancy.
- Conventional chondrosarcomas often show resistance to chemotherapy.
- Methylthioadenosine phosphorylase (MTAP) is crucial for adenine salvage and methionine synthesis; its deficiency sensitizes cells to purine synthesis inhibitors.
Purpose of the Study:
- To determine the frequency of MTAP gene deletions in conventional, grade II chondrosarcomas.
- To explore the potential for targeted therapy based on MTAP status.
Main Methods:
- Fluorescence in situ hybridization (FISH) analysis was performed on 23 patient samples of conventional, grade II chondrosarcoma.
- MTAP gene deletions (homozygous or hemizygous) were assessed.
Main Results:
- 61% of samples were evaluable for FISH analysis (14 out of 23).
- 50% of evaluable samples (7 out of 14) exhibited MTAP gene deletion.
- 43% of evaluable samples (6 out of 14) showed no deletion.
Conclusions:
- Approximately 50% of conventional, grade II chondrosarcomas may possess MTAP deletions.
- These MTAP-deleted chondrosarcomas could be sensitive to pharmacologic inhibitors of de novo purine synthesis.
- Findings informed a Phase II trial of pemetrexed for advanced chondrosarcomas.
