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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >Recurrent patterns of DNA methylation in the ZNF154, CASP8, and VHL promoters across a wide spectrum of human solid epithelial tumors and cancer cell lines
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Recurrent patterns of DNA methylation in the ZNF154, CASP8, and VHL promoters across a wide spectrum of human solid epithelial tumors and cancer cell lines

机译：ZNF154，CASP8和VHL启动子中的DNA甲基化在多种人类实体上皮肿瘤和癌细胞系中的复发模式

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The study of aberrant DNA methylation in cancer holds the key to the discovery of novel biological markers for diagnostics and can help to delineate important mechanisms of disease. We have identified 12 loci that are differentially methylated in serous ovarian cancers and endometrioid ovarian and endometrial cancers with respect to normal control samples. The strongest signal showed hypermethylation in tumors at a CpG island within the ZNF154 promoter. We show that hypermethylation of this locus is recurrent across solid human epithelial tumor samples for 15 of 16 distinct cancer types from TCGA. Furthermore, ZNF154 hypermethylation is strikingly present across a diverse panel of ENCODE cell lines, but only in those derived from tumor cells. By extending our analysis from the Illumina 27K Infinium platform to the 450K platform, to sequencing of PCR amplicons from bisulfite treated DNA, we demonstrate that hypermethylation extends across the breadth of the ZNF154 CpG island. We have also identified recurrent hypomethylation in two genomic regions associated with CASP8 and VHL. These three genes exhibit significant negative correlation between methylation and gene expression across many cancer types, as well as patterns of DNaseI hypersensitivity and histone marks that reflect different chromatin accessibility in cancer vs. normal cell lines. Our findings emphasize hypermethylation of ZNF154 as a biological marker of relevance for tumor identification. Epigenetic modifications affecting the promoters of ZNF154, CASP8, and VHL are shared across a vast array of tumor types and may therefore be important for understanding the genomic landscape of cancer.
机译：癌症中异常DNA甲基化的研究是发现用于诊断的新型生物学标记的关键，并且可以帮助描述疾病的重要机制。我们已经确定了相对于正常对照样品在浆液性卵巢癌和子宫内膜样卵巢癌和子宫内膜癌中差异甲基化的12个基因座。最强的信号显示ZNF154启动子内CpG岛的肿瘤中甲基化过度。我们显示该基因座的超甲基化在固体人上皮肿瘤样品中从TCGA的16种不同的癌症类型中有15种复发。此外，ZNF154高度甲基化惊人地存在于多种ENCODE细胞系中，但仅存在于肿瘤细胞中。通过将我们的分析从Illumina 27K Infinium平台扩展到450K平台，再从亚硫酸氢盐处理的DNA进行PCR扩增子测序，我们证明了高甲基化作用跨越了ZNF154 CpG岛的整个范围。我们还确定了与CASP8和VHL相关的两个基因组区域中的反复低甲基化。这三种基因在许多癌症类型之间的甲基化和基因表达之间，以及DNaseI超敏反应和组蛋白标记的模式之间均表现出显着的负相关性，反映了与正常细胞系相比，不同的染色质可及性。我们的发现强调ZNF154的高甲基化是与肿瘤鉴定相关的生物学标记。影响ZNF154，CASP8和VHL启动子的表观遗传修饰在多种肿瘤类型之间共享，因此对于理解癌症的基因组格局可能很重要。

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