Promoter hypermethylation of mismatch repair gene hMLH1 predicts the clinical response of malignant astrocytomas to nitrosourea
Promoter hypermethylation of mismatch repair gene hMLH1 predicts the clinical response of malignant astrocytomas to nitrosourea
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DOI：
10.1158/1078-0432.ccr-04-1625
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发表时间：
2005-02-15
影响因子：
11.5
通讯作者：
Komine, C
中科院分区：
文献类型：
--
作者：
Fukushima, T;Katayama, Y;Komine, C
用途：在某些类型的人类癌症中，启动子超甲基化导致的hMLH 1转录失活在错配修复功能的丧失中起着因果作用，错配修复功能调节细胞毒性途径以响应DNA损伤剂。本研究的目的是探讨hMLH 1基因启动子甲基化在恶性星形细胞瘤中的作用。我们检测了41例恶性星形细胞瘤患者的hMLH 1启动子甲基化，这些患者均接受了1-（4-氨基-2-甲基-5-嘧啶基）甲基-3-2（2-氯乙基）-3-亚硝基脲化疗联合放疗和干扰素治疗，并评估这种甲基化与临床结果的相关性。在41例新诊断的恶性星形细胞瘤中，6例（15%）发现hMLHI启动子甲基化. hMLHI启动子的高甲基化与hMLH 1蛋白免疫组化染色的缺失密切相关（P = 0.0013）。与hMLH 1-未甲基化肿瘤患者相比，hMLH 1-甲基化肿瘤患者对辅助治疗的反应机会更大（P = 0.0150）。单因素分析（P = 0.0340）和多因素分析（P 0.0161）显示hMLH 1甲基化的存在与较长的无进展生存期显著相关。结论：本研究确定hMLH 1甲基化状态是恶性星形细胞瘤对基于氯乙基亚硝基脲的辅助治疗的临床反应的预测因子。研究结果表明，hMLH 1甲基化状态的测定可以为设计合理的化疗策略以及预测预后提供潜在的依据。
Purpose: In certain types of human cancers, transcriptional inactivation of hMLH1 by promoter hypermethylation plays a causal role in the loss of mismatch repair functions that modulate cytotoxic pathways in response to DNA-damaging agents. The aim of the present study was to investigate the role of promoter methylation of the hMLH1 gene in malignant astrocytomas.Experimental Design: We examined the hMLH1 promoter methylation in a homogeneous cohort of patients with 41 malignant astrocytomas treated by 1-(4-amino-2-methyl5-pyrimidinyl)methyl-3-2(2-chloroethyl)-3-nitrosourea chemotherapy in combination with radiation and interferon therapy, and assessed the correlation of such methylation with clinical outcome.Results: hMLHI promoter methylation was found in 6 (15 %) of the 41 newly diagnosed malignant astrocytomas. Hypermethylation of the hMLHI promoter corresponded closely with a loss of immunohistochemical staining for hMLH1 protein (P = 0.0013). Patients with hMLH1-methylated tumors displayed a greater chance of responding to adjuvant therapy as compared with those with hMLH1-unmethylated tumors (P = 0.0150). The presence of hMLHI hypermethylation was significantly associated with a longer progression-free survival on both univariate analysis (P = 0.0340) and multivariate analysis (P 0.0161).Conclusions: The present study identified hMLH1 methylation status as a predictor of the clinical response of malignant astrocytomas to chloroethylnitrosourea-based adjuvant therapy. The findings obtained suggest that determination of the methylation status of hMLH1 could provide a potential basis for designing rational chemotherapeutic strategies, as well as for predicting prognosis.