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Clinical Cancer Research Vol. 8, 782-787, March 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Methylthioadenosine Phosphorylase Gene Deletions Are Common in Osteosarcoma1

José M. García-Castellano2,3, Alberto Villanueva2, John H. Healey, Rebecca Sowers, Carlos Cordon-Cardo, Andrew Huvos, Joseph R. Bertino, Paul Meyers and Richard Gorlick4

Orthopaedic Surgery Service, affiliated with Weil Medical College of Cornell University [J. M. G-C., J. H. H.], and Laboratory of Signal Transduction [A. V.], Departments of Pediatrics [R. S., P. M., R. G.], Pathology [C. C-C., A. H.], and Molecular Pharmacology and Therapeutics Program [J. R. B.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Purpose: 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 p15INK4b and p16INK4a. The aim of this study was to investigate the frequency of molecular alterations in MTAP in osteosarcoma.

Experimental Design: 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.

Result: 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.




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Copyright © 2002 by the American Association for Cancer Research.