Aberrant methylation and loss of expression of O-methylguanine-DNA methyltransferase in pulmonary squamous cell carcinoma and adenocarcinoma.

O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that protects cells against the carcinogenic effects of alkylating agents. The methylation status of the MGMT gene was investigated by methylation-specific polymerase chain reaction (PCR) and expression status was investigated by immunohistochemistry in 70 cases of pulmonary squamous cell carcinoma (pulmonary SqCC), including 23 cases of the central type and 47 cases of the peripheral type, and in 53 cases of the peripheral type of pulmonary adenocarcinoma (AC). The frequency of MGMT methylation was 36% in SqCC and 42% in AC. Cases with MGMT methylation correlated significantly with T factor in SqCC (P = 0.047) and AC (P = 0.03). In SqCC, the frequency of MGMT methylation was 26% in the central type and 40% in the peripheral type; a significant correlation was not found (P = 0.29). In AC with mixed subtypes showing MGMT methylation, the level of MGMT expression in the bronchioloalveolar carcinoma (BAC) area (non-invasive status) was significantly higher than that in the papillary or acinar AC area (invasive status; P = 0.0002). This trend was not found in AC with mixed subtypes showing no MGMT methylation (P = 0.10). These findings suggest that MGMT inactivation is an event that occurs in the late carcinogenic process in SqCC and AC, and that AC progress from non-invasive status to invasive status with MGMT inactivation induced by the promoter DNA methylation.