O-6-methylguanine-DNA methyltransferase promoter hypermethylation shifts the p53 mutational spectrum in non-small cell lung cancer

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) remove s mutagenic adducts from the O6 position of guanine, thereby protecting the genome against G to A transition mutations. MGMT is inactivated by promote r hypermethylation in many human cancers and has been associated with G to A mutations in K-ras in colorectal cancer. We hypothesized that MGMT promot er hypermethylation would be associated with an increase in G to A transiti ons in the p53 gene in non-small cell lung cancer (NSCLC). p53 mutations we re detected by both dideoxy sequencing and p53 GeneChip analysis in 92 pati ents with primary NSCLC. Methylation of the promoter region of the MGMT gen e was determined using methylation-specific PCR and was present in 27 of 92 (29%) tumors. Hypermethylation of the MGMT promoter was more common in ade nocarcinoma than in other histological types of NSCLC and was also more com mon in poorly differentiated tumors. MGMT promoter hypermethylation was pre sent significantly more often in tumors with a G to A mutation in p53 (9 of 14; 64%) than in tumors with other types of p53 mutations (11 of 41; 27%; P = 0.02) or in tumors with wild-type p53 (7 of 37; 18%; P = 0.006). MGMT p romoter hypermethylation was also strongly associated with G to A transitio ns at CpG sites. Inactivation of the MGMT gene by promoter hypermethylation alters the pattern of p53 mutation in NSCLC.