A MOLECULAR AND IMMUNOHISTOCHEMICAL STUDY OF THE MDM2 PROTEIN ISOFORMS AND P53 GENE-PRODUCT IN BRONCHOGENIC-CARCINOMA

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 techniqu es, The findings were correlated with the pathological features of the carcinomas, MDM2 protein was overexpressed in 26 cases (63 per cent), Western blot analysis with two monoclonal antibodies, 1B10 and IF2, r evealed three MDM2 protein isoforms, p90, p57 and p76/74, p90 and p57 are capable of interacting with p53 protein, while p76/74 is not, Vari ous patterns of MDM2 isoforms were seen, Although no correlation betwe en the patterns and pathological features was observed, lymph node met astases were more frequent in the cases with MDM2 overexpression (P<0. 005). In 3 out of 17 specimens of normal lung tissue examined, there w as a low level of expression of p90, Molecular analysis revealed that MDM2 overexpression was a consequence of increased transcription rathe r than MDM2 gene amplification, p53 protein was overexpressed in 21 ca ses (51 per cent) and p53 gene alterations (mutations + allelic deleti ons) were detected in 23 patients (56 per cent). A high degree of conc ordance (76 per cent) between p53 mutations and p53 staining was notic ed (P<10(-5)). p53 gene alterations were significantly associated with lymph node disease (P<0.01). MDM2 and p53 proteins were simultaneousl y detected in 21 cases (51 per cent), of which 17 (42 per cent) showed p53 and MDM2 overexpression, The latter group was positively correlat ed,vith p53 mutations (P<0.05). A strong correlation between MDM2/p53 co-expression and lymph node metastases was observed (P<0.001). The fi ndings suggest that MDM2 overexpression is a common event in bronchoge nic carcinoma, The selective expression of some MDM2 isoforms in neopl astic tissue and not in the surrounding normal areas underscores the p athological role of the various MDM2 products, Finally, the coexistenc e of MDM2 protein(s) and p53 aberrations (mutations and/or overexpress ion) in a subset of lung carcinomas may be indicative of a 'gain of fu nction' phenotype, with more aggressive characteristics.