MOLECULAR DAMAGE IN THE BRONCHIAL EPITHELIUM OF CURRENT AND FORMER SMOKERS

Background: Most lung cancers are attributed to smoking, These cancers have been associated with multiple genetic alterations and with the p resence of preneoplastic bronchial lesions, In view of such associatio ns, we evaluated the status of specific chromosomal loci in histologic ally normal and abnormal bronchial biopsy specimens from current and f ormer smokers and specimens from nonsmokers, Methods: Multiple biopsy specimens were obtained from 18 current smokers, 24 former smokers, an d 21 nonsmokers, Polymerase chain reaction-based assays involving 15 p olymorphic microsatellite DNA markers were used to examine eight chrom osomal regions for genetic changes (loss of heterozygosity [LOH] and m icrosatellite alterations), Results: LOH and microsatellite alteration s were observed in biopsy specimens from both current and former smoke rs, but no statistically significant differences were observed between the two groups. Among individuals with a history of smoking, 86% demo nstrated LOH in one or more biopsy specimens, and 24% showed LOH in al l biopsy specimens, About half of the histologically normal specimens from smokers showed LOH, but the frequency of LOH and the severity of histologic change did not correspond until the carcinoma in situ stage , A subset of biopsy specimens from smokers that exhibited either norm al or preneoplastic histology showed LOH at multiple chromosomal sites , a phenomenon frequently observed in carcinoma in situ and invasive c ancer, LOH on chromosomes 3p and 9p was more frequent than LOH on chro mosomes 5q, 17p (17p13; TP53 gene), and 13q (13q14; retinoblastoma gen e), Microsatellite alterations were detected in 64% of the smokers, No genetic alterations were detected in nonsmokers, Conclusions: Genetic changes similar to those found in lung cancers can be detected in the nonmalignant bronchial epithelium of current and former smokers and m ay persist for many years after smoking cessation.