Comparative methylome analysis of benign and malignant peripheral nerve sheath tumors
Comparative methylome analysis of benign and malignant peripheral nerve sheath tumors
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DOI：
10.1101/gr.109678.110
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发表时间：
2011-04-01
期刊：
影响因子：
7
通讯作者：
Beck, Stephan
中科院分区：
文献类型：
--
作者：
Feber, Andrew;Wilson, Gareth A.;Beck, Stephan
异常DNA甲基化（DNAm）在25年前首次与癌症有关。从那时起，许多研究将肿瘤抑制基因的高甲基化和癌基因的低甲基化与肿瘤发生过程联系起来。然而，这些研究大多局限于启动子和CpG岛（CGI）的分析。最近，全基因组DNAm（甲基化组）分析的新技术已经开发出来，能够对癌症甲基化组进行无偏分析。通过使用MeDIP-seq，我们报告了恶性外周神经鞘瘤（MPNSTs），良性神经纤维瘤和正常雪旺细胞的基于测序的比较甲基化组分析。对这些甲基化组的分析揭示了DNA m改变的复杂景观。与已报道的其他肿瘤类型相比，使用MeDIP-seq的甲基化组分析在MPNST中未观察到显著的整体低甲基化。然而，在卫星重复序列中发现了高度显著（P < 10（-100））的DNAm方向差异，表明这些重复序列是MPNSTs中低甲基化的主要靶点。MPNST和Schwann细胞甲基化组的比较分析确定了101，466个癌症相关的差异甲基化区域（cDMR）。分析显示，这些cDMR显著富集两种卫星重复类型（SATR 1和ARL α），并表明这些序列的异常DNAm与从健康细胞向恶性疾病的转变之间存在关联。还鉴定了CGI序列中高甲基化cDMR（P < 10（-60））、非CGI相关启动子（P < 10（-4））和SINE重复序列中低甲基化cDMR（P < 10（-100））的显著富集。整合DNAm和基因表达数据显示，与CGI海岸cDMR相关的基因的表达模式能够区分疾病表型。这项研究建立了MeDIP-seq作为分析癌症甲基化组的有效方法。
Aberrant DNA methylation (DNAm) was first linked to cancer over 25 yr ago. Since then, many studies have associated hypermethylation of tumor suppressor genes and hypomethylation of oncogenes to the tumorigenic process. However, most of these studies have been limited to the analysis of promoters and CpG islands (CGIs). Recently, new technologies for whole-genome DNAm (methylome) analysis have been developed, enabling unbiased analysis of cancer methylomes. By using MeDIP-seq, we report a sequencing-based comparative methylome analysis of malignant peripheral nerve sheath tumors (MPNSTs), benign neurofibromas, and normal Schwann cells. Analysis of these methylomes revealed a complex landscape of DNAm alterations. In contrast to what has been reported for other tumor types, no significant global hypomethylation was observed in MPNSTs using methylome analysis by MeDIP-seq. However, a highly significant (P < 10(-100)) directional difference in DNAm was found in satellite repeats, suggesting these repeats to be the main target for hypomethylation in MPNSTs. Comparative analysis of the MPNST and Schwann cell methylomes identified 101,466 cancer-associated differentially methylated regions (cDMRs). Analysis showed these cDMRs to be significantly enriched for two satellite repeat types (SATR1 and ARL alpha) and suggests an association between aberrant DNAm of these sequences and transition from healthy cells to malignant disease. Significant enrichment of hypermethylated cDMRs in CGI shores (P < 10(-60)), non-CGI-associated promoters (P < 10(-4)) and hypomethylated cDMRs in SINE repeats (P < 10(-100)) was also identified. Integration of DNAm and gene expression data showed that the expression pattern of genes associated with CGI shore cDMRs was able to discriminate between disease phenotypes. This study establishes MeDIP-seq as an effective method to analyze cancer methylomes.