Inactivation of O(6)‐Methylguanine‐DNA Methyltransferase in Human Lung Adenocarcinoma Relates to High‐grade Histology and Worse Prognosis among Smokers

To evaluate the significance of O(6)‐methylguanine‐DNA methyltransferase (MGMT) activity in the development of human lung adenocarcinoma (AC), we investigated promoter hypermethylation of the MGMTx gene by methylation‐specific PCR, and the expression of MGMT protein by immuno‐histochemistry in relation to smoking history of the patients. In total, 31 of 87 AC patients (35.5%) showed hypermethylation of the MGMT gene, and no significant difference was observed between smokers (37.3%) and non‐smokers (33.3%). However, hypermethylation of the MGMT gene increased in parallel with lesser differentiation grade of tumors among smokers (well, 16.7%; moderately, 42.1%; poorly, 57.1%; P=0.022), although this trend was not observed among non‐smokers. Almost all the tumors with promoter hypermethylation of the MGMT gene showed consistently negative MGMT staining by immunohistochemistry. When the prognosis of stage‐I patients was compared among smokers, it was apparent that the prognosis of patients with inactivated MGMT was worse than that of MGMT‐positive patients (P=0.036). Such differences in the prognoses were not observed among non‐smokers. In conclusion, MGMT inactivation is related to the differentiation grade and the prognosis of lung AC patients among smokers. Although further studies are required, we speculate that smoking may induce hypermethylation, not only of the MGMT gene, but also of other important tumor suppressor genes.