CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas.
CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas.
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DOI：
10.1158/0008-5472.828.65.3
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发表时间：
2005-02
期刊：
影响因子：
11.2
通讯作者：
Masanobu Abe;M. Ohira;Atsushi Kaneda;Y. Yagi;Seiichiro Yamamoto;Y. Kitano;T. Takato;A. Nakagawara;T. Ushijima
中科院分区：
文献类型：
--
作者：
Masanobu Abe;M. Ohira;Atsushi Kaneda;Y. Yagi;Seiichiro Yamamoto;Y. Kitano;T. Takato;A. Nakagawara;T. Ushijima
神经母细胞瘤是儿科最常见的实体瘤之一，以自发性消退和危及生命的进展两种极端病程为特征。在这里，我们进行了一项全基因组搜索，以寻找区分这两种类型的神经母细胞瘤的DNA甲基化差异。三个CpG岛(CGI)和两组CGI在神经母细胞瘤中特异性甲基化，预后不良。通过对140例独立病例的定量分析，发现5个CGI组的甲基化均密切相关，符合CpG岛甲基化表型(CIMP)的概念。CIMP的存在是通过PCDHB CGI的甲基化敏感地检测到的，并与显著的低存活率相关(危险比，22.1%可信区间，5.3%-93.4；P<；0.0001)。几乎所有N-myc扩增的病例(37/38)都表现为CIMP。即使在10 2例无N-myc扩增的病例中，CIMP(30例)的存在也预示着预后不良(危险性比为12.4；95%可信区间为2.6~5 8.9；P=0.002)。位于其基因体中的PCDHB CGI的甲基化不抑制基因表达或诱导组蛋白修饰。然而，CIMP与RASSF1A和BLU抑癌基因启动子CGI的甲基化显著相关。结果表明，合并CIMP的神经母细胞瘤预后较差，提示诱导重要基因沉默是其潜在机制。
Neuroblastoma, one of the most common pediatric solid tumors, is characterized by two extreme disease courses, spontaneous regression and life-threatening progression. Here, we conducted a genome-wide search for differences in DNA methylation that distinguish between neuroblastomas of the two types. Three CpG islands (CGI) and two groups of CGIs were found to be methylated specifically in neuroblastomas with a poor prognosis. By quantitative analysis of 140 independent cases, methylation of all the five CGI (groups) was shown to be closely associated with each other, conforming to the CpG island methylator phenotype (CIMP) concept. The presence of CIMP was sensitively detected by methylation of the PCDHB CGIs and associated with significantly poor survival (hazard ratio, 22.1; 95% confidence interval, 5.3-93.4; P < 0.0001). Almost all cases with N-myc amplification (37 of 38 cases) exhibited CIMP. Even in 102 cases without N-myc amplification, the presence of CIMP (30 cases) strongly predicted poor survival (hazard ratio, 12.4; 95% confidence interval, 2.6-58.9; P = 0.002). Methylation of PCDHB CGIs, located in their gene bodies, did not suppress gene expression or induce histone modifications. However, CIMP was significantly associated with methylation of promoter CGIs of the RASSF1A and BLU tumor suppressor genes. The results showed that neuroblastomas with CIMP have a poor prognosis and suggested induction of silencing of important genes as an underlying mechanism.