P53 AND MDM-2 EXPRESSION IN MALIGNANT-MELANOMA - AN IMMUNOCYTOCHEMICAL STUDY OF EXPRESSION OF P53, MDM-2, AND MARKERS OF CELL-PROLIFERATIONIN PRIMARY VERSUS METASTATIC TUMORS

Alterations in the function of p53, a tumor suppressor gene, have been postulated as a principal underlying mechanism involved in the loss o f cell cycle control in human malignancies. Because p53 dysfunction is generally associated with protein overexpression, immunocytochemistry is a valuable technique for the analysis of p53's functional status. We tested the hypothesis that loss of p53 function is a critical event in the early development and progression of human malignant melanoma and can lead to alterations in cell proliferation. We performed an imm unocytochemical study in archival fixed, embedded specimens that inclu ded 102 melanocytic lesions ranging from benign nevi to metastatic mel anoma. In addition to p53, we assessed the p53-associated protein, mdm -2, and markers of cell cycle status (the MIB-1-defined cell prolifera tion marker; proliferating cell nuclear antigen; and statin, a 57-kDa nuclear protein expressed preferentially by G0 cells). Tumor expressio n of all nuclear proteins was scored in a semiquantitative fashion rel ated to the fraction of positive tumor nuclei. The overall incidence o f significant p53 overexpression was low (8% of primary and 14% of met astatic melanomas). Analysis demonstrated strong correlation between i ncreasing p53 expression in primary versus metastatic lesions (chi(2) analysis, P = 0.001). Correlation was found between increased MIB-1-de fined cell proliferation and p53 overexpression in primary melanomas ( P = 0.02). Detectable mdm-2 expression was significantly correlated wi th p53 overexpression (P = 0.02). Comparison of statin and proliferati ng cell nuclear antigen indices demonstrated inverse correlation (chi( 2), P = 0.03) in the combined groups, but within the metastatic group there was a subset of cases strongly expressing the two markers. These studies suggest that the incidence of p53 dysfunction, possibly due t o endogenous protein binding rather than by mutation, increases with w orsening clinical course of melanoma and that the cell cycle becomes i ncreasingly dysregulated.