Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C→A:T mutations of the TP53 tumor suppressor gene
Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C→A:T mutations of the TP53 tumor suppressor gene
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DOI：
10.1093/carcin/22.10.1715
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发表时间：
2001-10-01
期刊：
影响因子：
4.7
通讯作者：
Ohgaki, H
中科院分区：
文献类型：
--
作者：
Nakamura, M;Watanabe, T;Ohgaki, H
O-6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)是一种修复蛋白，它能特异性地去除DNA中鸟嘌呤O-6位上的致突变烷基。肿瘤细胞修复O-6-烷基鸟嘌呤加合物与耐药性有关，因为它降低了烷化化疗药物的细胞毒性。我们通过甲基化特异性聚合酶链式反应评估了星形细胞脑瘤中MGMT基因启动子的甲基化。在54例低级别弥漫性星形细胞瘤(WHO II级)中26例(48%)和16例继发性胶质母细胞瘤(WHO IV级)中12例(75%)检测到MGMT启动子甲基化。原发(从头)胶质母细胞瘤中MGMT甲基化频率显著降低(13/36，36%，P=0.0155)。有MGMT甲基化的低级别星形细胞瘤大多数(24/26，92%)存在TP53突变，而28例无MGMT甲基化的星形细胞瘤中只有11例(39%)携带TP53突变(P<；0.0001)。低级别星形细胞瘤中有MGMT甲基化的G：C->；A：T突变频率(15/26，58%)明显高于未发生甲基化的星形细胞瘤(3/28，11%，P=0.0004)。这些结果表明，由于启动子甲基化而导致的MGMT表达缺失，通常发生在导致继发性胶质母细胞瘤的早期阶段，似乎与TP53突变的频率增加有关，特别是G：C->；A：T转换。
O-6-Methylguanine-DNA methyltransferase (MGMT) is a repair protein that specifically removes promutagenic alkyl groups from the O-6 position of guanine in DNA. Repair of O-6-alkylguanine adducts by tumour cells has been implicated in drug resistance since it reduces the cytotoxicity of alkylating chemotherapeutic agents. We assessed promoter methylation of the MGMT gene in astrocytic brain tumours by methylation-specific PCR. MGMT promoter methylation was detected in 26 of 54 (48%) low-grade diffuse astrocytomas (WHO grade II) and in 12 of 16 (75%) of secondary glioblastomas (WHO grade IV) that had progressed from low-grade astrocytomas. The frequency of MGMT methylation was significantly lower in primary (de novo) glioblastomas (13 of 36, 36%, P = 0.0155). The majority of low-grade astrocytomas with MGMT methylation (24/26, 92%) contained a TP53 mutation, whereas only 11 out of 28 (39%) cases without MGMT methylation carried a TP53 mutation (P < 0.0001). Furthermore, G:C --> A:T transition mutations at CpG sites were significantly more frequent in low-grade astrocytomas with MGMT methylation (15/26, 58%) than in those without (3/28, 11%, P = 0.0004). These results suggest that loss of MGMT expression as a result of promoter methylation, which frequently occurs at an early stage in the pathway leading to secondary glioblastomas, appears to be associated with increased frequency of TP53 mutations, in particular G:C --> A:T transitions.