These results are consistent with the hypothesis that MDM2 binds to p53, and that amplification of MDM2 in sarcomas leads to escape from p53-regulated growth control.
Three well-differentiated liposarcomas with MDM2 amplification coexisted with high-grade dedifferentiated sarcomas, in which MDM2 amplification was also observed.
Amplification of the MDM2 gene, which maps to chromosome band 12q13 and encodes a p53-binding protein, may result in functional inactivation of p53 and has been observed in various bone and soft tissue sarcomas.
Our knowledge of the molecular biology of sarcomas has progressed considerably over the past year, with major emphasis on the role of p53 and MDM2 gene mutations.
The cellular mdm2 gene, which has potential transforming activity that can be activated by overexpression, is amplified in a significant percentage of human sarcomas and in other mammalian tumors.
This study was designed to determine the prevalence and potential clinical value of detected molecular abnormalities and altered patterns of expression of mdm2 and p53 genes in adult soft tissue sarcomas.
However, CGH analysis detected amplification of 12q14 also in some tumors where neither MDM2 nor CDK4 was amplified, suggesting that another as yet unknown gene(s) may drive amplification of this region in sarcomas.
In this study, we have assessed the occurrence of p53, Rb and MDM2 alterations in the same samples of osteosarcomas, along with representative samples of various other sarcomas.
We have analyzed soft-tissue sarcomas (STS) molecularly for mutations in the tumor-suppressor gene p53 and immunohisto-chemically for expression of p53 and mdm2 proteins.
Because some sarcomas exhibit amplification and overexpression of MDM-2, which may interact with p53 and cause stabilization of wild-type p53 protein, we examined these tumors for MDM-2 amplification.
MDM2 is a wild-p53 inducible protein which may form a complex with p53, abrogating its function, as has been found in human sarcomas and other malignancies. p21WAF1/CIP1 is another protein inducible by wild-type p53, involved in inhibiting cell-cycle progression, through binding to cyclin/cyclin-dependent-kinase complexes.