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

Abstract

BackgroundRecent 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.MethodUsing 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.ResultsWe 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.ConclusionThis finding suggests a pivotal role for genetically driven changes in chromatin remodeling in shaping DNA methylation and gene expression patterns during tumor development.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0425-z) contains supplementary material, which is available to authorized users.

Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy

“…These observations raise questions about the cause of global hypomethylation and whether this might be related to DNMT expression. As reviewed elsewhere [45], a number of oncogenes are involved in the regulation of DNA methylation, but whether they are involved in hypomethylation of melanoma cell lines as highlighted here is unclear. Removal of methyl groups involves the TET family of dioxygenases followed by glycosylation and replacement with an unmethylated cytosine.…”

“…The ATRX-DNMT3-DNMT3L (ADD) domain of DNMT3A interacts with several transcription and epigenetic regulators, such as the EZH2 and SUV39H1 methyltransferases, HDAC1, heterochromatin protein 1 (HP1), PU.1 transcription factor (lymphoid specific enhancer), Myc, and p53 [43]. The literature on this topic has suggested that kinase cascades associated with PI3K/ AKT pathways can have direct effects on DNMTs in liver, stomach, and lung cancer cells in vitro [44,45]. In other instances, the effects of DNMTs have been speculated to be mediated by EZH2the catalytic subunit of polycomb repressive complex 2 (PRC2) and a known target of AKT [46].…”

Construction of a Comprehensive Multiomics Map of Hepatocellular Carcinoma and Screening of Possible Driver Genes

“…Similar to our study, they also found that TP53, ARID1A, PTEN, and other genes were significantly mutated in HCC samples. In another study, the authors used data from 20 cancer types in TCGA to identify methylation driver genes and expression driver genes (Youn et al, 2018), and there is some overlap with our results. Therefore, these results can be cross-validated, further confirming the reliability of our research.…”

Cancer methylomes characterization enabled by Rocker-meth

“…Several studies had presented comprehensive characterization of DNA-methylation across multiple cancer types while focusing on the analysis of single CpG sites [38,[59][60][61][62][63]. Here, we drafted the first pan-cancer catalog of DMRs based on the characterization of more than 6,000 human samples DNA methylation data of 14 tumor types from TCGA and other recent studies.…”