Forty-one bronchogenic carcinomas were investigated for expression of MDM2 protein isoforms and their relationship to p53 protein levels and p53 gene alterations using molecular and immunohistochemical techniques. The findings were correlated with the pathological features of the carcinomas. MDMZ protein was overexpressed in 26 cases (63 per cent). Western blot analysis with two monoclonal antibodies, lBlO and IF2, revealed three MDM2 protein isoforms, p90, p57 and p76/74. p90 and p57 are capable of interacting with p53 protein, while ~76174 is not. Various patterns of MDM2 isoforrns were seen. Although no correlation between the patterns and pathological features was observed, lymph node metastases were more frequent in the cases with MDM2 overexpression (P<0.005). In 3 out of 17 specimens of normal lung tissue examined, there was a low level of expression of p90. Molecular analysis revealed that MDMZ overexpression was a consequence of increased transcription rather than MDM2 gene amplification. p53 protein was overexpressed in 21 cases (51 per cent) andp53 gene alterations (mutations+allelic deletions) were detected in 23 patients (56 per cent). A high degree of concordance (76 per cent) between p53 mutations and p53 staining was noticed (PC 10 -5). p53 gene alterations were significantly associated with lymph node disease (PCO.01). MDMZ and p53 proteins were simultaneously detected in 21 cases (51 per cent), of which 17 (42 per cent) showed p53 and MDMZ overexpression. The latter group was positively correlated with p53 mutations (PCO.05). A strong correlation between MDM2/p53 co-expression and lymph node metastases was observed (P<O.OOl). The findings suggest that MDM2 overexpression is a common event in bronchogenic carcinoma. The selective expression of some MDM2 isoforms in neoplastic tissue and not in the surrounding normal areas underscores the pathological role of the various MDMZ products. Finally, the coexistence of MDMZ protein(s) and p53 aberrations (mutations andlor overexpression) in a subset of lung carcinomas may be indicative of a 'gain of function' phenotype, with more aggressive characteristics.
KEY WORDS-MDMZ protein isoforms; MDMZ gene amplification; p53 gene alterations, lung carcinoma