Altered global methylation of DNA: An epigenetic difference in susceptibility for lung cancer is associated with its progression

Alterations in global DNA methylation have been observed in many cancers, b ut whether such alterations represent an epigenetic difference in susceptib ility for the disease is unknown. The status of global DNA methylation also has not been reported in intact or specific types of cells involved in the carcinogenic process. To address these issues in lung carcinogenesis, we e valuated the status of global DNA methylation by using a monoclonal antibod y specific for 5-methylcytosine (5-mc) in randomly selected lung specimens of 60 cigarette smokers who developed squamous cell carcinoma (SCC) and 30 cigarette smokers who did not. 5-mc immunostaining scores of DNA of SCC (0. 61 +/- 0.42) and associated hyperplastic lesions (0.82 +/- 0.27) was signif icantly lower than those of DNA of histologically normal bronchial epitheli al cells (0.99 +/- 0.52) and hyperplastic lesions (1.2 +/- 0.22) of noncanc er specimens. The ratio of 5-mc scores between SCC and matched uninvolved b ronchial epithelial cells was significantly associated with advanced stage and size of the tumor. The results suggest that alteration in global DNA me thylation is an important epigenetic difference in susceptibility for the d evelopment of lung cancer. The reduced global DNA methylation in SCC compar ed with epithelial hyperplasia and its association with tumor size and dise ase stage is suggestive of its involvement in the progression of SCC. The r esults also indicate that normal methylation of DNA in epithelial hyperplas tic lesions may prevent the transformation of these lesions to invasive can cer. If these results are confirmed, the status of DNA methylation in early lesions such as epithelial hyperplasia could be used to identify smokers w ho are at risk for the development of SCC. HUM PATHOL 32:856-862. (C) 2001 by W.B. Saunders Company.