Aberrant methylation of multiple genes in neuroblastic tumours:: relationship with MYCN amplification and allelic status at 1p
Aberrant methylation of multiple genes in neuroblastic tumours:: relationship with MYCN amplification and allelic status at 1p
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DOI：
10.1016/s0959-8049(03)00312-5
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发表时间：
2003-07-01
影响因子：
8.4
通讯作者：
Rey, JA
中科院分区：
文献类型：
--
作者：
Gonzalez-Gomez, P;Bello, MJ;Rey, JA
异常甲基化发生在肿瘤细胞CpG岛上，是癌症中基因转录抑制的重要途径。我们研究了甲基化特异性聚合酶链反应（PCR）的11个基因的异常超甲基化，亚硫酸氢盐处理后的DNA，并与MYCN扩增和等位基因状态在一系列的44个神经母细胞肿瘤在1 p的研究结果。该肿瘤系列包括5例神经节神经瘤（G）、1例神经节神经母细胞瘤（GN）和38例神经母细胞瘤（6例1期肿瘤; 5例2期肿瘤; 6例3期病例; 19例4期肿瘤和2例4S期病例）。在95%（44例中的42例）的病例中检测到所研究的11个基因中至少有一个基因的异常甲基化。异常甲基化的发生率分别为：血小板反应蛋白1（THBS1）64%，金属蛋白酶组织抑制因子3（TIMP-3）30%，O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）27%，p73 25%，RB1 18%，死亡相关蛋白激酶（DAPK）、p14（ARF）、p16（INK4a）和半胱天冬酶8为14%，TP53和谷胱甘肽S-转移酶P1（GSTP1）为0%。在四个对照正常组织样本（脑和肾上腺髓质）中未观察到异常甲基化。MYCN扩增发现在11例（所有4期神经母细胞瘤），而等位基因损失在16个样本（13个4期和2个3期神经母细胞瘤，和一个节细胞神经瘤）。除1例半胱天冬酶8甲基化外，所有病例均显示MYCN扩增。我们的研究结果表明，启动子高甲基化是一种常见的表观遗传事件在成神经细胞肿瘤的肿瘤发生，但没有特定的模式的高甲基化基因可以证明。(C)2003爱思唯尔科技有限公司版权所有。
Aberrant hypermethylation occurs in tumour cell CpG islands and is an important pathway for the repression of gene transcription in cancers. We investigated aberrant hypermethylation of 11 genes by methylation-specific polymerase chain reaction (PCR), after treatment of the DNA with bisulphite, and correlated the findings with MYCN amplification and allelic status at 1 p in a series of 44 neuroblastic tumours. This tumour series includes five ganglioneuromas (G), one ganglioneuroblastoma (GN) and 38 neuroblastomas (six stage 1 tumours; five stage 2 tumours; six stage 3 cases; 19 stage 4 tumours, and two stage 4S cases). Aberrant methylation of at least one of the 11 genes studied was detected in 95 % (42 of 44) of the cases. The frequencies of aberrant methylation were: 64% for thrombospondin-1 (THBS1); 30% for tissue inhibitor of metalloproteinase 3 (TIMP-3); 27% for O-6-methylguanine-DNA methyltransferase (MGMT); 25% for p73; 18% for RB1; 14% for death-associated protein kinase (DAPK), p14(ARF), p16(INK4a) and caspase 8, and 0% for TP53 and glutathione S-transferase P1 (GSTP1). No aberrant methylation was observed in four control normal tissue samples (brain and adrenal medulla). MYCN amplification was found in 11 cases (all stage 4 neuroblastomas), whereas allelic loss at 1p was identified in 16 samples (13 stage 4 and two stage 3 neuroblastomas, and one ganglioneuroma). All but one case with caspase 8 methylation also displayed MYCN amplification. Our results suggest that promoter hypermethylation is a frequent epigenetic event in the tumorigenesis of neuroblastic tumours, but no specific pattern of hypermethylated genes could be demonstrated. (C) 2003 Elsevier Science Ltd. All rights reserved.