Intratumoral homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas
Intratumoral homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas
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DOI：
10.1002/ijc.23020
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发表时间：
2007-12-01
影响因子：
6.4
通讯作者：
Kretzschmar, Hans A.
中科院分区：
文献类型：
--
作者：
Grasbon-Frodl, Eva M.;Kreth, Friedrich Wilhelm;Kretzschmar, Hans A.
DNA修复基因06 -甲基-鸟嘌呤DNA甲基转移酶（MGMT）的超甲基化与使用烷化剂治疗的胶质母细胞瘤患者的生存期延长有关。目的是前瞻性分析恶性胶质瘤的MGMT状态是否可以从小尺寸立体定向活检（最大体积：1 mm 3）中确定。特别关注的是MGMT启动子甲基化的肿瘤内分布，MGMT蛋白表达和两者之间的潜在相关性。纳入了25例成人患者（20例原发性世界卫生组织（WHO）III级或IV级恶性胶质瘤患者，5例继发性恶性胶质瘤患者）。从肿瘤内的不同部位收集每个肿瘤约2-4个活检标本。通过甲基化特异性PCR（IMSP）和亚硫酸氢钠测序，对采集的每份标本（标本总数：69份）中MGMT基因的启动子甲基化进行评估。这两种方法都经过验证，适用于小尺寸组织样品（1 mm 3）。免疫组化法检测MGMT蛋白表达。新发组的总体MGMT启动子甲基化率为30%，肿瘤进展组为80%。MSP和测序的成功率分别为100%和80%。序列分析和MSP显示100%一致的结果。在25名患者中的24名中，在每个肿瘤的不同样本之间没有检测到MGMT启动子甲基化的差异。由于坏死组织污染活检标本，获得了1个假阴性结果。从每个肿瘤的不同部位采集的组织样本（研究的13个肿瘤）显示出相同或高度相似的MGMT蛋白表达。MGMT基因启动子甲基化与MGMT蛋白表达无相关性。恶性胶质瘤的MGMT启动子甲基化状态可以通过小尺寸的立体定向活检可靠地确定。MSP和亚硫酸氢钠测序所定义的甲基化谱构成了恶性胶质瘤的均一标记。MGMT状态和MGMT蛋白表达之间缺乏相关性需要进一步评估。(C)2007 Wiley-Liss，Inc.
Hypermethylation of the DNA repair gene 06 -methyl-guanine DNA methyltransferase (MGMT) has been linked to prolonged survival in glioblastoma patients treated with alkylating agents. It was aimed to analyze prospectively whether the MGMT status of malignant gliomas could be determined from small-sized stereotactic biopsies (maximum volume: 1 mm 3). Special attention was directed towards the intratumoral distribution of the MGMT promoter methylation, the MGMT protein expression and potential correlations between both. Twenty-five adult patients were included (20 patients with primary World Health Organisation (WHO) Grade III or IV malignant gliomas, 5 patients with secondary malignant gliomas). About 2-4 biopsy specimens per tumor were collected from different sites within the tumor. Promoter methylation of the MGMT gene was assessed by methylation-specific PCR IMSP) and sodium bisullite sequencing in each of the collected specimens (overall number of specimens: 69). Both methods were validated for application in small-sized tissue samples (1 mm 3). The MGMT protein expression was analyzed by immunohistochemistry. The overall MGMT promoter methylation rate was 30% in the de novo group and 80% in the tumor progression group. The success rates of MSP and sequencing were 100% and 80%, respectively. Sequence analysis and MSP exhibited 100% concordant findings. No differences in MGMT promoter methylation were detected between the different samples of each individual tumor in 24 of 25 patients. One false negative result was obtained due to the contamination of the biopsy specimen by necrotic tissue. Tissue samples taken from different sites of each individual tumor (13 tumors investigated) exhibited equal or highly similar MGMT protein expression. No correlation between MGMT protein expression and MGMT promoter methylation was observed. The MGMT promoter methylation status of malignant gliomas can be reliably determined from small-sized stereotactic biopsies. The methylation profile, as defined by MSP and sodium bisulfite sequencing, constitutes a homogeneous marker throughout malignant gliomas. The lack of correlation between MGMT status and MGMT protein expression needs further evaluation. (C) 2007 Wiley-Liss, Inc.