Abstract
Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.
Highlights
Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer
partially methylated domains (PMDs) have been described for a variety of cancer types and appear to represent repressive chromatin domains that are associated with nuclear lamina interactions, late replication, and low transcription
Chromosomes 1 and X were exceptionally prone to methylation loss, the latter of which may be related to epigenetic aberrations of the inactive X-chromosome in breast cancer observed by others[18]
Summary
Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. The distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. Questions remain as to what instigates such focal hypermethylation, whether loss of methylation inside PMDs is linked to repression of cancer-relevant genes and whether the genomic distribution of PMDs is invariant throughout primary tumors of the same type, perhaps determined by tissue-of-origin. A major limitation of most DNA methylation studies is that only a small subset of CpGs are interrogated This prevents accurate determination of the extent and location of PMDs. Few samples of a certain tissue/tumor have typically been analyzed using whole-genome bisulfite sequencing (WGBS). We show that PMDs define breast cancer methylomes and are linked to other key epigenetic aberrations such as CGI hypermethylation
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