title: Methylthioadenosine phosphorylase gene deletions are common in osteosarcoma.
abstract: OBJECTIVE
  Methylthioadenosine phosphorylase (MTAP) is an enzyme essential in the salvage of cellular adenine and methionine synthesis. The MTAP gene is located in the 9p21 chromosomal region and its loss is frequently associated with deletion of the tumor suppressor genes p15(INK4b) and p16(INK4a). The aim of this study was to investigate the frequency of molecular alterations in MTAP in osteosarcoma.
  
  
  METHODS
  Samples from patients with high-grade osteosarcoma (n = 96) and three osteosarcoma cell lines (HOS, SaOS-2, and U2OS) were analyzed. Genomic DNA was analyzed for MTAP gene deletions by PCR, RNA expression was measured by semiquantitative reverse transcription-PCR, and the protein levels were measured by immunohistochemistry.
  
  
  RESULTS
  Deletion of at least one MTAP exon was found in 36 of 96 (37.5%) osteosarcoma patient samples and in one of the three cell lines (HOS). In all cases in which an MTAP gene deletion was observed, there was absence of detectable mRNA and protein. Furthermore, in four osteosarcoma patients, an MTAP deletion which was not evident at diagnosis was detected in subsequent tumor samples.
  
  
  CONCLUSIONS
  The MTAP gene is commonly deleted in osteosarcoma patient samples, leading to an absence of mRNA and protein expression; these results indicate that inhibitors of de novo purine synthesis or methionine depletion may be effective as treatments for osteosarcoma patients whose tumors fail to express MTAP.
authors.affiliation: Orthopaedic Surgery Service, affiliated with Weil Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: José M
authors.initials: JM
authors.lastname: García-Castellano
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sowers
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Andrew
authors.initials: A
authors.lastname: Huvos
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
authors.forename: Paul
authors.initials: P
authors.lastname: Meyers
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
mesh_terms: D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics*; D018797:Cell Cycle Proteins; D002648:Child; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D005091:Exons; D005260:Female; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000502:physiology; D025521:Tumor Suppressor Proteins
chemical_list: C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase