A pan-cancer analysis of driver gene mutations, DNA methylation and gene expressions reveals that chromatin remodeling is a major mechanism inducing global changes in cancer epigenomes.
A pan-cancer analysis of driver gene mutations, DNA methylation and gene expressions reveals that chromatin remodeling is a major mechanism inducing global changes in cancer epigenomes.
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DOI：
10.1186/s12920-018-0425-z
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发表时间：
2018-11-06
影响因子：
2.7
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Youn A;Kim KI;Rabadan R;Tycko B;Shen Y;Wang S
最近的大规模癌症测序研究在人类癌症中发现了许多新的癌症驱动基因（CDG）。一些研究还表明，CDG突变有助于许多癌症类型中与癌症相关的表观基因组和转录组学改变。在这里，我们的目标是提高我们对CDG突变和改变的癌细胞表观基因组和转录组之间的联系的理解，以及这些联系如何有助于表观基因组和转录组之间的已知关联。使用多组学数据，包括来自癌症基因组图谱（TCGA）项目的20种癌症类型的体细胞突变，DNA甲基化和基因表达数据，我们进行了泛癌症分析，以确定CDG，当突变时，与癌症类型的全基因组甲基化或表达变化有很强的关联，我们分别将其称为甲基化驱动基因（MDGs）或表达驱动基因（EDGs）。我们确定了32个MDGs，其中8个是已知的染色质修饰或重塑基因。其余24个MDG中的许多都通过调节它们的转录或作为潜在的辅助因子与它们物理相互作用而与染色质调节因子相关联。我们确定了29个电子讨论组，其中26个也是千年发展目标。进一步对这26个重叠驱动基因的启动子甲基化和表达变化模式的研究表明，目标基因启动子的高甲基化与相同目标基因的下调显著相关，目标基因启动子的低甲基化与相同目标基因的上调显著相关。这一发现表明，遗传驱动的染色质重塑变化在肿瘤发展过程中塑造DNA甲基化和基因表达模式中起着关键作用。本文的在线版本（10.1186/s12920-018-0425-z）包含补充材料，可供授权用户使用。
Recent large-scale cancer sequencing studies have discovered many novel cancer driver genes (CDGs) in human cancers. Some studies also suggest that CDG mutations contribute to cancer-associated epigenomic and transcriptomic alterations across many cancer types. Here we aim to improve our understanding of the connections between CDG mutations and altered cancer cell epigenomes and transcriptomes on pan-cancer level and how these connections contribute to the known association between epigenome and transcriptome. Using multi-omics data including somatic mutation, DNA methylation, and gene expression data of 20 cancer types from The Cancer Genome Atlas (TCGA) project, we conducted a pan-cancer analysis to identify CDGs, when mutated, have strong associations with genome-wide methylation or expression changes across cancer types, which we refer as methylation driver genes (MDGs) or expression driver genes (EDGs), respectively. We identified 32 MDGs, among which, eight are known chromatin modification or remodeling genes. Many of the remaining 24 MDGs are connected to chromatin regulators through either regulating their transcription or physically interacting with them as potential co-factors. We identified 29 EDGs, 26 of which are also MDGs. Further investigation on target genes’ promoters methylation and expression alteration patterns of these 26 overlapping driver genes shows that hyper-methylation of target genes’ promoters are significantly associated with down-regulation of the same target genes and hypo-methylation of target genes’ promoters are significantly associated with up-regulation of the same target genes. This finding suggests a pivotal role for genetically driven changes in chromatin remodeling in shaping DNA methylation and gene expression patterns during tumor development. The online version of this article (10.1186/s12920-018-0425-z) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
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