P53 ALTERATIONS IN ATYPICAL ALVEOLAR HYPERPLASIA OF THE HUMAN LUNG

Atypical alveolar hyperplasia (AAH) is a potential precursor lesion fr om which lung adenocarcinomas arise and may be a good target for study ing the early events of lung tumorigenesis. We have previously shown t hat AAHs are neoplastic epithelial proliferations that often harbor ac tivating mutations of the K-ras oncogene. In the current study, we exa mined a spectrum of AAHs to determine the frequency and timing of p53 alterations in lung tumorigenesis. We analyzed 37 AAHs and their paire d overt lung neoplasms for p53 protein accumulation using the monoclon al antibody DO7. DNA sequence analysis of the p53 gene was performed o n those cases demonstrating p53 protein accumulation. AAHs were classi fied as low-grade, high-grade, or AAH-like carcinoma based on cytoarch itectural features. Accumulation of the p53 protein was found in none (0%) of 20 low-grade AAHs, in 1 (Sro) of 11 high-grade AAHs, and in th ree (50%) of six AAH-like carcinomas. There was a statistically signif icant trend toward p53 accumulation with increasing grade of the AAHs. A missense mutation in exon 7 of the p53 gene was found in 1 AAH-like carcinoma, whereas mutations in exons 5 through 8 could not be detect ed in the other three AAHs with p53 protein accumulation. Three of the paired overt carcinomas harbored p53 mutations that were not present in the AAHs. Alterations of p53 do not appear to be common events in A AHs, especially when these lesions exhibit low-grade cytoarchitectural features. Alterations of p53, however, are more frequent at the level of AAH-like carcinoma and may be associated with the transition from a benign to a malignant proliferation of pneumocytes. Copyright (C) 19 98 by W.B. Saunders Company.