Abstract
Trends in altered DNA methylation have been defined across human cancers, revealing global loss of methylation (hypomethylation) and focal gain of methylation (hypermethylation) as frequent cancer hallmarks. Although many cancers share these trends, little is known about the specific differences in DNA methylation changes across cancer types, particularly outside of promoters. Here, we present a comprehensive comparison of DNA methylation changes between two distinct cancers, endometrioid adenocarcinoma (EAC) and glioblastoma multiforme (GBM), to elucidate common rules of methylation dysregulation and changes unique to cancers derived from specific cells. Both cancers exhibit significant changes in methylation over regulatory elements. Notably, hypermethylated enhancers within EAC samples contain several transcription factor binding site clusters with enriched disease ontology terms highlighting uterine function, while hypermethylated enhancers in GBM are found to overlap active enhancer marks in adult brain. These findings suggest that loss of original cellular identity may be a shared step in tumorigenesis.
Highlights
Trends in altered DNA methylation have been defined across human cancers, revealing global loss of methylation and focal gain of methylation as frequent cancer hallmarks
Complete DNA methylomes were generated for a total of five glioblastoma multiforme (GBM) samples[26], two normal frontal cortex brain samples[26], three endometrioid adenocarcinoma (EAC) samples[25], and one normal endometrial sample pooled from ten healthy individuals[25]
differentially methylated regions (DMRs) were classified as either cancer-type unique (DMR present in only one of the two cancers) or shared between EAC and GBM, resulting in 6 categories: EAC-unique hyperDMRs, EAC-unique hypomethylated DMR (hypoDMR), GBM-unique hyperDMRs, GBM-unique hypoDMRs, shared hyperDMRs, and shared hypoDMRs
Summary
Trends in altered DNA methylation have been defined across human cancers, revealing global loss of methylation (hypomethylation) and focal gain of methylation (hypermethylation) as frequent cancer hallmarks. We present a comprehensive comparison of DNA methylation changes between two distinct cancers, endometrioid adenocarcinoma (EAC) and glioblastoma multiforme (GBM), to elucidate common rules of methylation dysregulation and changes unique to cancers derived from specific cells. Both cancers exhibit significant changes in methylation over regulatory elements. To better understand how epigenetic abnormalities differ between cancers in both location and function, we directly compared deeply profiled DNA methylomes of two distinct cancer types, GBM and endometrioid adenocarcinoma (EAC), whose DNA methylation abnormalities have been previously identified[25,26].
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