Functional epigenetic approach identifies frequently methylated genes in Ewing sarcoma
Functional epigenetic approach identifies frequently methylated genes in Ewing sarcoma
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DOI：
10.4161/epi.26266
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发表时间：
2013-11-01
期刊：
影响因子：
3.7
通讯作者：
Latif, Farida
中科院分区：
文献类型：
--
作者：
Alholle, Abdullah;Brini, Anna T.;Latif, Farida
最近，我们使用候选基因的方法确定了与尤文肉瘤（ES）总生存率低相关的RASSF 2基因频繁甲基化。为了在全基因组范围内鉴定ES中的有效生物标志物，我们使用了功能上经过验证的表观遗传方法，其中通过用去甲基化剂处理在ES细胞系中诱导基因表达，然后杂交到高密度基因表达微阵列上。在遵循严格的选择标准后，选择34个基因用于ES细胞系和原代ES中的表达和甲基化分析。8个基因（CTHRC 1、DNAJA 4、ECHDC 2、NEFH、NPTX 2、PHF 11、RARRES 2、TSGA 14）在ES肿瘤中显示甲基化频率>20%（范围24-71%），这些基因在人骨髓来源的间充质干细胞（hBMSC）中表达，并且超甲基化与转录沉默相关。NPTX 2或PHF 11甲基化与ES预后不良相关。此外，上述基因中的6个在骨肉瘤中也显示甲基化频率>20%（范围36-50%）。这些基因的鉴定可能为骨癌肿瘤发生和表观遗传生物标志物的发展提供见解，用于这些罕见肿瘤类型的预后和检测。
Using a candidate gene approach we recently identified frequent methylation of the RASSF2 gene associated with poor overall survival in Ewing sarcoma (ES). To identify effective biomarkers in ES on a genome-wide scale, we used a functionally proven epigenetic approach, in which gene expression was induced in ES cell lines by treatment with a demethylating agent followed by hybridization onto high density gene expression microarrays. After following a strict selection criterion, 34 genes were selected for expression and methylation analysis in ES cell lines and primary ES. Eight genes (CTHRC1, DNAJA4, ECHDC2, NEFH, NPTX2, PHF11, RARRES2, TSGA14) showed methylation frequencies of >20% in ES tumors (range 24-71%), these genes were expressed in human bone marrow derived mesenchymal stem cells (hBMSC) and hypermethylation was associated with transcriptional silencing. Methylation of NPTX2 or PHF11 was associated with poorer prognosis in ES. In addition, six of the above genes also showed methylation frequency of >20% (range 36-50%) in osteosarcomas. Identification of these genes may provide insights into bone cancer tumorigenesis and development of epigenetic biomarkers for prognosis and detection of these rare tumor types.