Yin Dong, Xie Dong, Hofmann Wolf-Karsten, Zhang Wenxuan, Asotra Kamlesh, Wong Rex, Black Keith L, Koeffler H Phillip
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048, USA.
Mol Carcinog. 2003 Jan;36(1):23-31. doi: 10.1002/mc.10094.
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.
DNA修复酶O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）可从鸟嘌呤的O(6)位去除烷基化加合物，保护细胞免受细胞毒性和诱变作用。在某些癌症中MGMT的表达会降低，这可能是该基因启动子和编码区的CpG岛甲基化的结果。我们使用甲基化特异性聚合酶链反应（PCR）研究了大量脑肿瘤样本（85个）中MGMT启动子的甲基化状态。在85个人脑肿瘤样本中，48%出现异常甲基化。定量实时PCR显示，在MGMT基因启动子区域发生甲基化的脑肿瘤中，MGMT mRNA水平的表达显著降低（P < 0.001）。MGMT可通过从鸟嘌呤的O(6)位去除烷基来预防G到A的突变。我们发现，与MGMT启动子未甲基化的脑肿瘤相比，MGMT启动子甲基化的脑肿瘤中p53基因G:C到A:T突变的频率显著增加（P < 0.05），并且p53所有非CpG二核苷酸G:C到A:T突变均出现在MGMT启动子甲基化的样本中。
