O6-methylguanine-DNA methyltransferase promoter methylation in 45 primary central nervous system lymphomas: quantitative assessment of methylation and response to temozolomide treatment
O6-methylguanine-DNA methyltransferase promoter methylation in 45 primary central nervous system lymphomas: quantitative assessment of methylation and response to temozolomide treatment
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DOI：
10.1007/s11060-011-0721-3
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发表时间：
2012-03-01
影响因子：
3.9
通讯作者：
Nishikawa, Ryo
中科院分区：
文献类型：
--
作者：
Adachi, Jun-ichi;Mishima, Kazuhiko;Nishikawa, Ryo
最近有报道称，对大剂量甲氨蝶呤治疗无效的原发性中枢神经系统淋巴瘤（PCNSL）患者对替莫唑胺化疗有良好的反应。编码DNA修复酶O（6）-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的基因在几种人类肿瘤（包括神经胶质瘤和系统性淋巴瘤）中因启动子甲基化而转录沉默。MGMT启动子甲基化也是接受替莫唑胺治疗的胶质母细胞瘤患者的预后标志物。为了验证替莫唑胺在PCNSL中的治疗，我们应用甲基化敏感性高分辨率熔解（MS-HRM）分析来定量PCNSL中的MGMT甲基化。在45例PCNSL患者中，23例（51%）的肿瘤中检测到MGMT启动子甲基化，其中11例被认为具有高甲基化状态（超过70.0%）。在接受替莫唑胺治疗的5例复发性PCNSL中，4例缓解，3例完全缓解，1例部分缓解。所有四个响应PCNSL甲基化MGMT启动子，而非响应复发PCNSL没有。因此，使用定量MS-HRM分析检测MGMT启动子甲基化已被首次建议在PCNSL。该检测方法可以快速和高通量的MGMT甲基化状态的评估，似乎是有前途的临床设置。MGMT启动子甲基化可能成为预测PCNSL对替莫唑胺反应的有用标志物。
Favorable responses to temozolomide chemotherapy have recently been reported in primary central nervous system lymphoma (PCNSL) patients who are refractory to high-dose methotrexate therapy. The gene encoding the DNA repair enzyme O (6)-methylguanine-DNA methyltransferase (MGMT) is transcriptionally silenced by promoter methylation in several human tumors, including gliomas and systemic lymphomas. MGMT promoter methylation is also a prognostic marker in glioblastoma patients treated with temozolomide. To validate temozolomide treatment in PCNSL, we applied methylation-sensitive high resolution melting (MS-HRM) analysis to quantitate MGMT methylation in PCNSL. MGMT promoter methylation was detected in tumors from 23 (51%) of 45 PCNSL patients, 11 of which were considered to have high (more than 70.0%) methylation status. Of the five recurrent PCNSLs treated with temozolomide, four cases responded, with three achieving complete response and one, a partial response. All four responsive PCNSLs had methylated MGMT promoters, whereas the non-responsive recurrent PCNSL did not. Thus, the use of quantitative MS-HRM analysis for the detection of MGMT promoter methylation has been suggested in PCNSL for the first time. The assay allows rapid and high-throughput evaluation of the MGMT methylation status, and seems to be promising in clinical settings. MGMT promoter methylation may become a useful marker for predicting the response of PCNSLs to temozolomide.