AMPLIFICATION OF THE CDK4 GENE IN SARCOMAS - TUMOR SPECIFICITY AND RELATIONSHIP WITH THE RB GENE MUTATION

Amplification of the CDK4 gene, which encodes a key molecule in the ce ll cycle, has been shown in some types of human neoplasms, including b one and soft tissue tumors. It is also reported that the CDK4 gene is coamplified with other sequences in the 12q13-15 region, including the MDM2 and SAS genes. Using 146 DNA samples derived from a variety of b one and soft tissue tumors, we have studied the pattern of amplificati on of these three genes, CDK4, MDM2, and SAS, to investigate whether t here are any tumor type specific patterns of amplification. Amplificat ion of at least one of these three genes was found in 18 tumors, and f ive different patterns of amplification were observed Amplification of all of these three genes was detected in 9 cases. Amplification of th e CDK4 gene without MDM2 amplification was observed in osteosarcomas a nd a chondrosarcoma but not in soft tissue rumors, whereas amplificati on of MDM2 gene alone was, observed in malignant fibrous histiocytomas (MFHs) liposarcomas, and lipomas, but not in bone tumors. these resul ts suggested that the CDK4 region is the primary target for amplificat ion in bone tumors, whereas the MDM2 region is in soft tissue tumors. We also investigated the relationship of CDK4 amplification with retin oblastoma (RB) gene mutations in osteosarcomas, for which we have alre ady performed the mutation analyses in detail. Interestingly, contrary to the prevailing theory that CDK4 amplification is an alternative me chanism for RE gene mutation, we found that three of four cases with a mplification of the CDK4 gene showed loss of expression of the RE prot ein one of which was proved to have an guess DNA alteration in the RE locus. This redundancy of mutations may indicate that the amplificatio n of CDK4 may have some roles other than the inactivation of the RB pr otein in the development of osteosarcomas.