Esteller Manel, Herman James G
Cancer Epigenetics Laboratory, Molecular Pathology Program, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain.
Oncogene. 2004 Jan 8;23(1):1-8. doi: 10.1038/sj.onc.1207316.
O(6)-methylguanine DNA methyltransferase (MGMT) is a key enzyme in the DNA repair network. MGMT removes mutagenic and cytotoxic adducts from O(6)-guanine in DNA, the preferred point of attack of many carcinogens (i.e. methylnitrosourea) and alkylating chemotherapeutic agents (i.e. BCNU, temozolamide, etc.). Hypermethylation of the CpG island located in the promoter region of MGMT is primarily responsible for the loss of MGMT function in many tumor types. The methylation-mediated silencing of MGMT has two consequences for cancer. First, tumors with MGMT methylation have a new mutator phenotype characterized by the generation of transition point mutations in genes involved in cancer etiology, such as the tumor suppressor p53 and the oncogene K-ras. Second, MGMT hypermethylation demonstrates the possibility of pharmacoepigenomics: methylated tumors are more sensitive to the killing effects of alkylating drugs used in chemotherapy. These recent results underscore the importance of MGMT in basic and translational cancer research.
O(6)-甲基鸟嘌呤DNA甲基转移酶（MGMT）是DNA修复网络中的关键酶。MGMT可从DNA中的O(6)-鸟嘌呤上去除诱变和细胞毒性加合物，O(6)-鸟嘌呤是许多致癌物（如甲基亚硝基脲）和烷化剂化疗药物（如卡莫司汀、替莫唑胺等）的首选攻击位点。位于MGMT启动子区域的CpG岛的高甲基化是许多肿瘤类型中MGMT功能丧失的主要原因。MGMT甲基化介导的沉默对癌症有两个影响。首先，MGMT甲基化的肿瘤具有新的突变体表型，其特征是在参与癌症病因的基因（如肿瘤抑制基因p53和癌基因K-ras）中产生转换点突变。其次，MGMT高甲基化证明了药物表观基因组学的可能性：甲基化的肿瘤对化疗中使用的烷化剂的杀伤作用更敏感。这些最新结果强调了MGMT在基础和转化癌症研究中的重要性。
