Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy
Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy
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DOI：
10.1038/sj.bjc.6605127
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发表时间：
2009-06-30
影响因子：
8.8
通讯作者：
Walker, C.
中科院分区：
文献类型：
--
作者：
Dunn, J.;Baborie, A.;Walker, C.
背景：启动子甲基化对o -6-甲基鸟嘌呤- dna甲基转移酶（MGMT）的表观遗传沉默与烷基化剂治疗的胶质母细胞瘤患者生存率的提高有关。在这项研究中，我们研究了在英国单一治疗中心接受替莫唑胺和放疗治疗的胶质母细胞瘤的MGMT启动子甲基化。方法：通过焦磷酸测序获得109个胶质母细胞瘤的单个CpG位点的定量甲基化数据。结果：中位总生存期（OS）为12.4个月，2年生存率为17.9%。焦磷酸测序数据与所有胶质母细胞瘤的档案样本可重复。观察到离散CpG位点甲基化模式的变化和肿瘤内甲基化异质性。109个胶质母细胞瘤中有58个至少在一个临床样本中显示平均甲基化>非肿瘤性脑；86%在多个样品中具有均匀甲基化状态。甲基化是与延长无进展生存期（PFS）和OS相关的独立预后因素。甲基化超过35%的患者有最长的生存期（中位PFS 19.2个月；OS 26.2个月，2年生存率59.7%）。中度或高度甲基化与非甲基化患者的PFS有显著差异，而低、中度或高度甲基化患者的OS均有显著差异。结论：这些数据表明，MGMT甲基化在常规临床放化疗的胶质母细胞瘤中具有重要的预后意义；此外，甲基化程度可用于提供额外的预后分层。英国癌症杂志（2009）101,124-131。doi: 10.1038 / sj.bjc。6605127 www.bjcancer.com 2009年6月16日在线发布(C) 2009年英国癌症研究中心
BACKGROUND: Epigenetic silencing of O-6-methylguanine-DNA- methyltransferase (MGMT) by promoter methylation is associated with improved survival in glioblastomas treated with alkylating agents. In this study, we investigated MGMT promoter methylation in glioblastomas treated with temozolomide and radiotherapy in a single UK treatment centre.METHODS: Quantitative methylation data at individual CpG sites were obtained by pyrosequencing for 109 glioblastomas.RESULTS: Median overall survival ( OS) was 12.4 months with 2-year survival of 17.9%. Pyrosequencing data were reproducible with archival samples yielding data for all glioblastomas. Variation in methylation patterns of discrete CpG sites and intratumoral methylation heterogeneity were observed. A total of 58 out of 109 glioblastomas showed average methylation >non-neoplastic brain in at least one clinical sample; 86% had homogeneous methylation status in multiple samples. Methylation was an independent prognostic factor associated with prolonged progression-free survival (PFS) and OS. Cases with methylation more than 35% had the longest survival (median PFS 19.2; OS 26.2 months, 2-year survival of 59.7%). Significant differences in PFS were seen between those with intermediate or high methylation and unmethylated cases, whereas cases with low, intermediate or high methylation all showed significantly different OS.CONCLUSIONS: These data indicate that MGMT methylation is prognostically significant in glioblastomas given chemoradiotherapy in the routine clinic; furthermore, the extent of methylation may be used to provide additional prognostic stratification. British Journal of Cancer ( 2009) 101, 124-131. doi: 10.1038/sj.bjc.6605127 www.bjcancer.com Published online 16 June 2009 (C) 2009 Cancer Research UK