Abstract
BackgroundOne of the most important recent findings in cancer genomics is the identification of novel driver mutations which often target genes that regulate genome-wide chromatin and DNA methylation marks. Little is known, however, as to whether these genes exhibit patterns of epigenomic deregulation that transcend cancer types.ResultsHere we conduct an integrative pan-cancer-wide analysis of matched RNA-Seq and DNA methylation data across ten different cancer types. We identify seven tumor suppressor and eleven oncogenic epigenetic enzymes which display patterns of deregulation and association with genome-wide cancer DNA methylation patterns, which are largely independent of cancer type. In doing so, we provide evidence that genome-wide cancer hyper- and hypo- DNA methylation patterns are independent processes, controlled by distinct sets of epigenetic enzyme genes. Using causal network modeling, we predict a number of candidate drivers of cancer DNA hypermethylation and hypomethylation. Finally, we show that the genomic loci whose DNA methylation levels associate most strongly with expression of these putative drivers are highly consistent across cancer types.ConclusionsThis study demonstrates that there exist universal patterns of epigenomic deregulation that transcend cancer types, and that intra-tumor levels of genome-wide DNA hypomethylation and hypermethylation are controlled by distinct processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0699-9) contains supplementary material, which is available to authorized users.
Highlights
One of the most important recent findings in cancer genomics is the identification of novel driver mutations which often target genes that regulate genome-wide chromatin and DNA methylation marks
Previous studies have already shown that a subset of these epigenetic enzyme (EE) genes exhibit differential expression in cancer (e.g., [18]), we wanted to re-assess this using a more comprehensive list of EE genes and using fresh high-quality RNA-Seq data from The Cancer Genome Atlas (TCGA) consortium
We identified a total of 62 EE genes which were consistently deregulated across at least eight of the ten cancer types, with 35 of these upregulated and representing putative oncogenes, and with the remaining 27 exhibiting downregulation (Fig. 2)
Summary
One of the most important recent findings in cancer genomics is the identification of novel driver mutations which often target genes that regulate genome-wide chromatin and DNA methylation marks. Many epigenetic enzymes (EEs), including chromatin modifiers, have been found to exhibit genetic mutations in cancer, often resulting in a genome-wide deregulation of the DNA methylation (DNAm) landscape [2,3,4,5,6]. Alteration of genome-wide DNAm and gene expression patterns has been observed in acute monocytic leukemias carrying DNMT3A mutations [7]. Another example is mutation of IDH1 (isocitrate dehydrogenase 1), which establishes a hypermethylator phenotype in glioma [8, 9].
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