Association of O6-Methylguanine-DNA Methyltransferase (MGMT) Promoter Methylation with p53 Mutation Occurrence in Non-Small Cell Lung Cancer with Different Histology, Gender, and Smoking Status

Abstract

O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been demonstrated to associate with the G:C-->A:T transition mutation in the p53 gene of lung tumors. The purpose of this study is to clarify whether MGMT promoter methylation is not only associated with the shift from the G:C-->A:T mutation in the p53 gene but also whether MGMT increases other mutation patterns in lung tumors. To further verify whether a different prevalence of MGMT promoter methylation is observed in lung tumors with a different tumor histology, gender, and smoking status, 220 lung tumors were collected to evaluate the status of MGMT promoter methylation and p53 mutation using methylation-specific PCR (MSP) and direct sequencing, respectively. The data shows that a higher prevalence of MGMT promoter methylation was observed in tumors with the G:C-->A:T transition or other p53 mutation patterns compared with those with p53 wild-type (P < 0.001 for G:C-->A:T; P = 0.015 for other mutation patterns), and this prevalence was more pronounced in tumors from male than from female patients. MGMT promoter methylation in p53 mutation patterns had a different effect on squamous cell carcinomas (SCC) and adenocarcinomas (ADC). Interestingly, the highest prevalence of MGMT promoter methylation was found in male nonsmokers followed by male smokers and female nonsmokers. This may be a partial explanation for the reason why male nonsmokers had a higher p53 mutation occurrence than female nonsmokers. MGMT promoter methylation may associate with increased occurrence of p53 mutation including the G:C-->A:T transition and other p53 mutation patterns in lung cancer, especially among male nonsmokers.