Epigenetic instability of imprinted genes in human cancers.
Epigenetic instability of imprinted genes in human cancers.
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DOI：
10.1093/nar/gkv867
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发表时间：
2015-12-15
影响因子：
14.9
通讯作者：
Lee S
中科院分区：
文献类型：
--
作者：
Kim J;Bretz CL;Lee S
由于与胰岛素和胰岛素样生长因子信号通路的功能联系，许多印迹基因在人类癌症中经常受到表观遗传影响。因此，目前的研究系统地表征了多种人类癌症中印迹基因的表观遗传不稳定性。首先，TCGA （the Cancer Genome Atlas）的调查结果显示，与正常细胞相比，原发肿瘤中大多数印迹基因的表达水平下调。这些变化还伴随着一些印迹结构域（如PEG3、MEST和GNAS结构域）的DNA甲基化水平变化。其次，使用几组癌症DNA进一步手工确认这些DNA甲基化水平的变化。结果表明，PEG3、MEST和GNAS结构域的印迹控制区确实在乳腺癌、肺癌和卵巢癌中受到影响。这项DNA甲基化调查还显示，在正常细胞和癌细胞中，这些印迹结构域中进化上保守的顺式调控元件是非常可变的。总的来说，这项研究强调了人类癌症中印迹结构域的表观遗传不稳定性，并进一步表明其作为癌症生物标志物的潜在用途。
Many imprinted genes are often epigenetically affected in human cancers due to their functional linkage to insulin and insulin-like growth factor signaling pathways. Thus, the current study systematically characterized the epigenetic instability of imprinted genes in multiple human cancers. First, the survey results from TCGA (The Cancer Genome Atlas) revealed that the expression levels of the majority of imprinted genes are downregulated in primary tumors compared to normal cells. These changes are also accompanied by DNA methylation level changes in several imprinted domains, such as the PEG3, MEST and GNAS domains. Second, these DNA methylation level changes were further confirmed manually using several sets of cancer DNA. According to the results, the Imprinting Control Regions of the PEG3, MEST and GNAS domains are indeed affected in breast, lung and ovarian cancers. This DNA methylation survey also revealed that evolutionarily conserved cis-regulatory elements within these imprinted domains are very variable in both normal and cancer cells. Overall, this study highlights the epigenetic instability of imprinted domains in human cancers and further suggests its potential use as cancer biomarkers.