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

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.