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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

Youn, Ahrim; Kim, Kyung In; Rabadan, Raul; Tycko, Benjamin; Shen, Yufeng; Wang, Shuang

Background
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.

Method
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.

Results
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.

Conclusion
This finding suggests a pivotal role for genetically driven changes in chromatin remodeling in shaping DNA methylation and gene expression patterns during tumor development.

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Also Published In

Title
BMC Medical Genomics
DOI
https://doi.org/10.1186/s12920-018-0425-z

More About This Work

Academic Units
Biostatistics
Systems Biology
Biomedical Informatics
Columbia Genome Center
Published Here
April 2, 2019

Notes

Pan-cancer analysis, TCGA, somatic mutation, DNA methylation, gene expression, methylation driver gene, expression driver gene, chromatic remodeling

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