MOLECULAR AND IMMUNOHISTOCHEMICAL IDENTIFICATION OF P53 ALTERATIONS IN BONE AND SOFT-TISSUE SARCOMAS

p53 has been shown to suppress tumor growth by regulating the cell cyc le and by triggering apoptosis. Acquired somatic mutations of the p53 gene have been observed in a variety of human malignancies, and these result in a loss of its tumor suppressor function. To examine the occu rrence of p53 abnormalities in bone and soft tissue sarcomas, 113 tumo rs were subjected to molecular analysis and mutations were confirmed i n 16 tumors. The frequency of p53 alterations varied among the differe nt subtypes of bone and soft tissue sarcomas, being observed predomina ntly in osteosarcomas (8/34 cases), rhabdomyosarcomas (2/3 cases), Ewi ng's sarcomas (1/5 cases), and liposarcomas (3/21 cases). In contrast, p53 gene mutations were detected at a lower frequency in malignant fi brous histiocytomas (2/34 cases) and not at all in nine chondrosarcoma s and five leiomyosarcomas. Immunohistochemical staining of p53 protei n was performed on 69 cases and compared to the DNA results. For 64 ca ses the results were concordant: 56 sarcomas were considered to have w ild-type p53 by both techniques. As well, increased p53 protein expres sion was observed in eight of the nine tumors with p53 gene mutations. However, positive p53 staining was also seen in four sarcomas which h ad no detectable p53 mutations in exons 5 through 9. Because some sarc omas exhibit amplification and overexpression of MDM-2, which may inte ract with p53 and cause stabilization of wild-type p53 protein, we exa mined these tumors for MDM-2 amplification. None of the tumors with MD M-2 amplification exhibited p53 immunopositivity. Very weak p53 reacti vity was detected in four malignant fibrous histiocytomas that had rec eived either chemotherapy or radiotherapy. Of 16 metastatic lesions ex amined, only one contained a p53 mutation. In addition, for five cases in which both the original lesion and its metastasis were analyzed, p 53 alterations were not observed in the metastases if the tumor was wi ld-type at presentation. These data suggest that p53 alterations occur at different frequencies in various subtypes of sarcoma and, although detected in metastatic lesions, are not associated more frequently wi th progression.