p53 and MDM2 alterations in osteosarcomas: correlation with clinicopathologic features and proliferative rate. Alterations of the p53 gene and of MDM2, a gene coding for a p53 binding protein, have been implicated in the pathogenesis of osteosarcoma (OS).To determine the frequency of alterations of the p53/MDM2 pathway in OS and their possible correlation with clinicopathologic features, MDM2 copy number and p53 protein levels were determined in a series of 83 samples of OS by quantitative Southern blot analysis and immunohistochemistry, respectively.Positivity for p53 was found in 26.5% and MDM2 amplification in 6.6% of the samples analyzed in a mutually exclusive fashion with one exception. Overall, alterations of the p53/MDM2 pathway occurred in 34% of cases; p53 accumulation was not associated with a higher proliferative rate. The mean age of patients with p53 positive OS (40 years) was older than that of the p53 negative group (28 years) (P < 0.04). Furthermore, three of the four cases of OS arising in Paget's disease showed p53 accumulation.Alterations of the p53/MDM2 pathway are frequent in OS and usually represent mutually exclusive tumorigenic events. p53 does not appear to be a major determinant of proliferative rate in OS.