Analysis of somatic NF1 promoter methylation in plexiform neurofibromas and Schwann cells
Analysis of somatic NF1 promoter methylation in plexiform neurofibromas and Schwann cells
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DOI：
10.1016/j.cancergencyto.2004.08.016
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发表时间：
2005-03-01
影响因子：
--
通讯作者：
Wallace, MR
中科院分区：
文献类型：
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作者：
Fishbein, L;Eady, B;Wallace, MR
神经纤维瘤病1（NF1）是一种常染色体显性遗传疾病，其特征是神经纤维瘤。据信，两个NF 1等位基因必须失活作为肿瘤发生的第一步。然而，通常体细胞突变未被识别，这表明表观遗传变化如甲基化可能是某些肿瘤中的“第二次打击”。文献报道，在一些正常组织和一些与NF 1相关的皮肤和丛状神经纤维瘤中，NF 1启动子转录起始位点周围的区域完全未甲基化。我们分析了正常雪旺细胞（神经纤维瘤中克隆扩增的细胞类型）和具有不明体细胞突变的NF 1相关丛状肿瘤样本中NF 1启动子的甲基化状态。在转录起始位点周围的451 bp区域中，在18个肿瘤样品中的12个中的几个特定胞嘧啶处发现低水平的甲基化。总的来说，通过甲基化的表观遗传沉默似乎不是第二次打击的主要机制。然而，这项研究分析了最多数量的NF 1相关丛状肿瘤，并且是第一个包括雪旺细胞富集肿瘤培养物的研究，检测到了比以往任何报道更大的甲基化。这表明，甲基化，特别是在潜在的转录因子结合位点，在一些丛状神经纤维瘤中受到中度干扰，应进一步研究。(C)2005年爱思唯尔公司All rights reserved.
Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with the characteristic feature being the neurofibroma. It is believed that both NF1 alleles must be inactivated as the first step in tumorigenesis. However, often the somatic mutations are not identified, suggesting that epigenetic changes such as methylation could account for the "second hit" in some tumors. The literature reports that the region of the NF1 promoter surrounding the transcription start site is completely unmethylated in several normal tissues and some NF1-related dermal and plexiform neurofibromas. We analyzed the methylation state of the NF1 promoter in normal Schwann cells (the cell type clonally expanded in neurofibromas) and in NF1-related plexiform tumor samples with unidentified somatic mutations. In a region of 451 bp surrounding the transcription start site, a low level of methylation was found at several specific cytosines in 12 of 18 tumor samples. Overall, epigenetic silencing through methylation does not appear to be a major mechanism for the second hit. However, this study, which analyzed the largest number of NF1-related plexiform tumors and is the first to include Schwann cell-enriched tumor cultures, detected greater methylation than in any previous reports. This suggests that methylation, especially at potential transcription factor binding sites, is moderately perturbed in some plexiform neurofibromas and should be investigated further. (C) 2005 Elsevier Inc. All rights reserved.