Estudio de codeleción de los genes del locus 9p21, p15, p16 y MTAP en osteosarcomas humanos

The aim of this study was to investigate the frequency of molecular alterations in MTAP in osteosarcoma and its codeletion with the tumor suppressor genes p15INK4b and p16^INK4a. Osteosarcoma patient samples (n = 96) and three osteosarcoma cell lines were analyzed. DNA was analyzed for MTAP, p15^INK4b and p16^INK4a genes codeletions and expression was measured at the RNA and protein levels. Deletion of MTAP was found in 37.5 % of patient samples and in one of the three cell lines (HOS). It was always codeleted with the exon 1 of p15^INK4b. In all cases in which an MTAP gene deletion was observed there was absence of detectable mRNA and protein. In four osteosarcoma patients, an MTAP deletion which was not evident at diagnosis was delected in subsequent tumor samples. In the osteosarcoma cell lines with homozygous deletion of MTAP (HOS) a 10-fold greater sensitivity to chemotherapeutic agents which act on de novo synthesis of purines was observed. 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 treatment for osteosarcoma patients whose tumors fail to express MTAP.