CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas
CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas
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DOI：
10.1158/1078-0432.ccr-04-0392
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发表时间：
2004-08-01
影响因子：
11.5
通讯作者：
Esteller, M
中科院分区：
文献类型：
--
作者：
Paz, MF;Yaya-Tur, R;Esteller, M
目的：DNA修复酶O-6-甲基鸟嘌呤DNA甲基转移酶（MGMT）抑制烷化剂对肿瘤细胞的杀伤，其在癌细胞中的丢失与MGMT CpG岛的超甲基化有关。因此，MGMT的甲基化与原发性胶质瘤中对1，3-双（2-氯乙基）-1-亚硝基脲（BCNU）的临床反应相关。在这里，我们调查是否存在的MGMT甲基化在胶质瘤也是一个很好的预测反应的另一个紧急烷化剂，替莫唑胺实验设计：使用甲基化特异性PCR方法，我们评估了甲基化状态的MGMT在92胶质瘤患者谁收到替莫唑胺作为一线化疗或作为治疗复发。结果：在接受替莫唑胺作为一线化疗的胶质瘤患者中，MGMT启动子甲基化与临床反应呈正相关（n = 40）。12例MGMT甲基化肿瘤患者中有8例（66.7%）部分或完全缓解，而28例非甲基化肿瘤患者中有7例（25.0%; P = 0.030）。在接受BCNU（n = 35，P = 0.041）或丙卡巴肼/1-（2-氯乙基）-3-环己基-1-亚硝基脲（n = 17，P = 0.043）作为一线化疗的患者中，我们还发现MGMT甲基化与临床反应呈正相关。总体而言，如果我们将替莫唑胺、BCNU和丙卡巴肼/1-（2-氯乙基）-3-环己基-1-亚硝基脲作为一组，分析所有一线化疗治疗的临床反应与MGMT甲基化状态的关系，则MGMT高甲基化与部分或完全临床反应的存在密切相关（P < 0.001）。最后，MGMT甲基化状态确定在初始胶质瘤肿瘤没有相关性的临床反应替莫唑胺时，这种药物作为治疗复发（P = 0.729）。结论：MGMT甲基化预测的一线化疗与烷化剂替莫唑胺的原发性胶质瘤的临床反应。这些结果可能为人类脑肿瘤的更多定制治疗开辟了可能性。
Purpose: The DNA repair enzyme O-6-methylguanine DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents, and its loss in cancer cells is associated with hypermethylation of the MGMT CpG island. Thus, methylation of MGMT has been correlated with the clinical response to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in primary gliomas. Here, we investigate whether the presence of MGMT methylation in gliomas is also a good predictor of response to another emergent alkylating agent, temozolomide.Experimental Design: Using a methylation-specific PCR approach, we assessed the methylation status of the CpG island of MGMT in 92 glioma patients who received temozolomide as first-line chemotherapy or as treatment for relapses.Results: Methylation of the MGMT promoter positively correlated with the clinical response in the glioma patients receiving temozolomide as first-line chemotherapy (n = 40). Eight of 12 patients with MGMT-methylated tumors (66.7%) had a partial or complete response, compared with 7 of 28 patients with unmethylated tumors (25.0%; P = 0.030). We also found a positive association between MGMT methylation and clinical response in those patients receiving BCNU (n = 35, P = 0.041) or procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (n = 17, P = 0.043) as first-line chemotherapy. Overall, if we analyze the clinical response of all of the first-line chemotherapy treatments with temozolomide, BCNU, and procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea as a group in relation to the MGMT methylation status, MGMT hypermethylation was strongly associated with the presence of partial or complete clinical response (P < 0.001). Finally, the MGMT methylation status determined in the initial glioma tumor did not correlate with the clinical response to temozolomide when this drug was administered as treatment for relapses (P = 0.729).Conclusions: MGMT methylation predicts the clinical response of primary gliomas to first-line chemotherapy with the alkylating agent temozolomide. These results may open up possibilities for more customized treatments of human brain tumors.