title: DNA repair gene O6-methylguanine-DNA methyltransferase: promoter hypermethylation associated with decreased expression and G:C to A:T mutations of p53 in brain tumors.
abstract: The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) removes alkylating adducts from the O(6) position of guanine and protects cells from cytotoxic and mutagenic effects. Expression of MGMT is decreased in some cancers, which may be the result of methylation of CpG islands of both the promoter and coding regions of the gene. We studied the methylation status of the MGMT promoter in a very large collection of brain tumors (85) using methylation-specific polymerase chain reaction (PCR). Aberrant methylation occurred in 48% of 85 human brain tumor samples. Quantitative real-time PCR showed that expression of MGMT mRNA levels was significantly decreased (P < 0.001) in those brain tumors that had methylation of the promoter region of their MGMT gene. MGMT can prevent G to A mutations by removing alkyl groups from the O(6) position of guanine. We found a significantly increased frequency of G:C to A:T mutations of the p53 gene in brain tumors having a methylated MGMT promoter compared with those having an unmethylated MGMT promoter (P < 0.05), and all the non-CpG dinucleotide G:C to A:T mutations of p53 were in samples with a methylated MGMT promoter.
authors.affiliation: Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Yin
authors.forename: Dong
authors.initials: D
authors.lastname: Xie
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Asotra
authors.forename: Rex
authors.initials: R
authors.lastname: Wong
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D001483:Base Sequence; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics*; D019175:DNA Methylation; D017931:DNA Primers; D004260:DNA Repair; D006801:Humans; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D017931:DNA Primers; D019853:O(6)-Methylguanine-DNA Methyltransferase