title: Methylthioadenosine phosphorylase gene deletions are frequently detected by fluorescence in situ hybridization in conventional chondrosarcomas.
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.
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA. wchow@coh.org
authors.forename: Warren A
authors.initials: WA
authors.lastname: Chow
authors.forename: Victoria
authors.initials: V
authors.lastname: Bedell
authors.forename: Popsie
authors.initials: P
authors.lastname: Gaytan
authors.forename: Ernest
authors.initials: E
authors.lastname: Borden
authors.forename: John
authors.initials: J
authors.lastname: Goldblum
authors.forename: David
authors.initials: D
authors.lastname: Hicks
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Slovak
mesh_terms: D002813:Chondrosarcoma / Q000201:enzymology* / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007399:Interphase / Q000235:genetics; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics*
chemical_list: D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase