Methylthioadenosine phosphorylase (MTAP) gene deletions are frequent in chondrosarcomas

Abstract

9019 Background: Chondrosarcomas are the second most common primary malignant tumor of bone after osteogenic sarcomas. Conventional chemotherapy for non-low-grade chondrosarcomas is generally ineffective. MTAP is a ubiquitous enzyme that catalyzes the phosphorolysis of the nucleoside methylthioadenosine (MTA), which is generated during the synthesis of the polymines, spermidine and spermine. MTAP is an essential enzyme in the salvage pathway of adenine and in methionine synthesis. Cells lacking the MTAP gene are unable to salvage adenine from MTA, and therefore are more dependent upon the de novo synthesis of purines. Accordingly, the absence of MTAP function makes MTAP deficient cells more susceptible than wild-type cells to pharmacologic inhibitors of de novo purine synthesis. The MTAP gene locus has been mapped to chromosome locus 9p21. Homozygous deletions of MTAP have been reported in several hematologic and solid tumor malignancies. Based upon these observations, we investigated the frequency of MTAP deletions in non-low-grade chondrosarcomas by fluorescence in-situ hybridization (FISH) analysis. Methods: 23 grade 2 (intermediate-grade) chondrosarcoma patient samples from the Cleveland Clinic Foundation were analyzed for MTAP deletions. Results: Nuclei were successfully extracted from 14/23 samples (61% evaluable) for FISH analysis. 7/14 samples (50%) demonstrated a deletion of the MTAP gene, 6/14 (43%) failed to demonstrate a deletion, and 1/14 (7%) was inconclusive. Conclusions: These findings suggest that approximately one-half of grade 2 chondrosarcomas may be preferentially sensitive to pharmacologic inhibitors of de novo purine synthesis. This study has resulted in the development by the Intergroup Coalition Against Sarcomas of a phase II trial of pemetrexed, a multi-targeted anti-folate, for advanced chondrosarcomas. No significant financial relationships to disclose.