Increased loss of chromosome 9p21 but not p16 inactivation in primary non-small cell lung cancer from smokers

Epidemiological studies have demonstrated a causal association between toba cco use and carcinoma of the lung, and some genetic targets of the carcinog ens in cigarette smoke have been defined recently. We further examined the effect of cigarette smoking on the frequency of allelic losses on chromosom e 9p21 and the incidence of p16 inactivation. Chromosomal loss at 9p21-24 w as determined by microsatellite analysis using 14 markers in 47 patients wi th non-small cell lung cancer, In addition, p16 gene inactivation was deter mined by DNA sequence analysis, methylation-specific PCR, and immunohistoch emistry. Tumors from a group of nonsmokers (n = 14) were compared with tumo rs from a group of smokers (n = 33) matched for cell type, tumor stage, and gender. Allelic loss encompassing the p16 locus was present significantly (P = 0.01) more often in smokers (23 of 33 smokers, 70%) than in nonsmokers (4 of 14 nonsmokers, 28%), No significant differences in the frequency of p16 inactivation were observed between smokers and nonsmokers (45% versus 3 6%), However, homozygous deletion of the p16 gene locus and point mutation of p16 gene were only observed in tumors from smokers, whereas the p16 gene was inactivated in tumors from nonsmokers only through promoter hypermethy lation, Thus, inactivation of the p16 gene is a common event in all non-sma ll cell lung cancer, but the mechanism of gene alteration differs between s mokers and nonsmokers. The significant link between tobacco and loss of the p16 locus identifies additional genetic targets of smoking in the pathogen esis of lung cancer.