Evidence of cumulative gene losses with progression of premalignant epithelial lesions to carcinoma of the bronchus.

Human bronchial carcinoma is thought to develop through progressive stages from basal cell hyperplasia to squamous metaplasia, dysplasia, carcinoma in situ, and finally invasive cancer. In this study, we used tissue microdissection to examine loss of heterozygosity of chromosomes 3p21, 5q21, and 9p21 at each stage of the epithelial progression to invasive cancers. Forty-eight premalignant/malignant bronchial sites were biopsied from 13 patients (including 9 subjects without cancer) using fluorescence bronchoscopy. Eighteen sites with moderate/severe dysplasia in 6 patients were subjected to bronchoscopic and molecular follow-up during a 3-month to 2-year period. Seven separate cases of advanced non-small cell bronchial cancers were also analyzed. From the baseline biopsies, the prevalence of 3p and 9p deletions increased significantly from no deletion in the hyperplasia/metaplasia samples (n = 9) to 37 and 31% of the informative cases, respectively, in the dysplasia samples (n = 29), to 100 and 83%, respectively, for the carcinomas in situ (n = 6), and 100% in the invasive cancers (n = 11). Chromosome 5q deletion was significantly more frequent in invasive cancers (70% of the informative cases) as compared to carcinoma in situ (40%), dysplasias (33%), and hyperplasia/metaplasia samples (11%). The number of chromosome alterations also increased significantly from the lowest to the highest grade lesions, showing evidence of accumulation of genetic damage from one group to another. The molecular follow-up analysis showed that the same genomic alteration can persist in a given dysplastic bronchial area for several months or years, and that the persistence or the regression of the molecular abnormality is well correlated with the evolution of the disease on follow-up. Our results suggest that molecular analysis of bronchial biopsies obtained by fluorescence bronchoscopy may be a very useful means to study the natural history of preinvasive bronchial lesions and the outcome of interventions, such as with chemopreventive treatment.