Lung cancer is the end result of a multistep process in which genetic and molecular changes accompany, in an unknown temporal sequence, histological precursor (preinvasive) bronchial lesions. Biomarkers allowing prediction of the rate of progression of precursor lesions at different locations in the anatomical field may be clinically useful. Toward this aim, we analyzed, using immunohistochemistry, the expression of the p53 gene and of its transcriptional target genes bax, bcl2, and waf1 in preinvasive bronchial lesions from 69 patients with lung cancer and in similar lesions from 20 patients with no cancer progression. p53 accumulation occurred with increasing frequency, from 19% in mild dysplasia to 36% in moderate dysplasia and 59% in carcinoma in situ, and was exclusively observed in patients with p53-positive carcinoma. The higher frequency of the p53-positive immunophenotype in lesions adjacent to the p53-positive carcinoma, as compared to lesions distant from it, suggests that p53 mutant preneoplastic lesions had a higher rate of progression to invasion than did p53-negative lesions. Similar lesions in patients with no progression to lung cancer were all p53 negative. Bcl2 overexpression and Bax down-regulation, as shown by immunostaining, occurred in preinvasive lesions and were mainly maintained during invasion. The expressions of bax, bcl2, and waf1 did not correlate with p53 status. We conclude that p53 stabilization in preinvasive lesions has high predictive value for progression to invasion and that Bax/Bcl2 imbalance contributes to the clonal expansion during premalignant states.

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