Abstract
Background There is growing evidence that DNA methylation alterations contribute to carcinogenesis. While cancer tissue exhibits widespread DNA methylation changes, the proportion of tissue-specific versus tissue-independent DNA methylation alterations in cancer is unclear. In addition, it is unknown which factors determine the patterns of aberrant DNA methylation in cancer.ResultsUsing HumanMethylation450 BeadChips (450k), we here analyze genome-wide DNA methylation patterns of ten types of fetal tissue, in addition to matched normal-cancer data for corresponding tissue types, encompassing over 3000 samples. We demonstrate that the level of aberrant cancer DNA methylation in gene promoters and gene bodies is highly correlated between cancer types. We estimate that up to 60 % of the DNA methylation variation in a cancer genome of a given tissue type is explained by the corresponding variation in a cancer genome of another type, implying that much of the cancer DNA methylation landscape is tissue independent. We further show that histone marks in normal cells are better predictors of aberrant cancer DNA methylation than the corresponding signals in human embryonic stem cells. We build predictors of cancer DNA methylation patterns and show that although inclusion of three histone marks (H3K4me3, H3K27me3 and H3K36me3) improves model accuracy, the bivalent marks are the most predictive. Finally, we show that chromatin accessibility of gene promoters in normal tissue dictates the promoter’s propensity to acquire aberrant DNA methylation in cancer in so far as it determines its level of DNA methylation in normal tissue.ConclusionsOur data show that a considerable fraction of the aberrant cancer DNA methylation landscape results from a mechanism that is largely tissue specific. Histone marks as specified in the normal cell of origin provide highly predictive models of aberrant cancer DNA methylation and outperform those derived from the same marks in hESCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0058-4) contains supplementary material, which is available to authorized users.
Highlights
There is growing evidence that DNA methylation alterations contribute to carcinogenesis
Cancerassociated hypermethylation of gene promoters has been shown to be more frequent at genes that are bivalently or PRC2 marked in human embryonic stem cells [11,12,13], and this appears to be a universal signature across all types of cancer
The propensity for promoter hypermethylation and gene‐body hypomethylation is highly correlated across cancer types In order to understand the molecular rules which determine aberrant de novo DNA methylation (DNAm) in cancer, we decided to follow the strategy of Nejman et al [16] and to focus on a background set of genomic sites which exhibit constitutively normal DNAm levels in a ground state
Summary
There is growing evidence that DNA methylation alterations contribute to carcinogenesis. While cancer tissue exhibits widespread DNA methylation changes, the proportion of tissue-specific versus tissue-independent DNA methylation alterations in cancer is unclear. It is unknown which factors determine the patterns of aberrant DNA methylation in cancer. Characteristic features of the cancer epigenome include promoter hypermethylation [4] and large mega-base scale blocks of hypomethylation [5,6,7,8], which often coincide with lamina-associated domains (LADs) [9] and domains of heterochromatin (H3K9me and H3K9me3) termed LOCKs [10]. Hypermethylation at bivalently or PRC2-marked gene promoters, and large-scale block hypomethylation are characteristic features of the DNAm landscape of aged normal tissue [14, 15]. Given that age is a major risk factor for many
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