Abstract
Although single base-pair resolution DNA methylation landscapes for embryonic and different somatic cell types provided important insights into epigenetic dynamics and cell-type specificity, such comprehensive profiling is incomplete across human cancer types. This prompted us to perform genome-wide DNA methylation profiling of 22 samples derived from normal tissues and associated neoplasms, including primary tumors and cancer cell lines. Unlike their invariant normal counterparts, cancer samples exhibited highly variable CpG methylation levels in a large proportion of the genome, involving progressive changes during tumor evolution. The whole-genome sequencing results from selected samples were replicated in a large cohort of 1112 primary tumors of various cancer types using genome-scale DNA methylation analysis. Specifically, we determined DNA hypermethylation of promoters and enhancers regulating tumor-suppressor genes, with potential cancer-driving effects. DNA hypermethylation events showed evidence of positive selection, mutual exclusivity and tissue specificity, suggesting their active participation in neoplastic transformation. Our data highlight the extensive changes in DNA methylation that occur in cancer onset, progression and dissemination.
Highlights
Over the last decade, genetic research has moved on from the use of targeted approaches to the routine application of exome and genome sequencing
In order to gain a comprehensive insight into the variation in DNA methylation between normal tissue types and alterations occurring in different cancer contexts, we performed genomewide profiling of 22 human samples using whole-genome bisulfite sequencing (WGBS)
WGBS creates DNA methylation profiles at base-pair resolution to give an unbiased overview of the DNA methylation landscape
Summary
Genetic research has moved on from the use of targeted approaches to the routine application of exome and genome sequencing. Despite an identical genomic blueprint, cells develop into phenotypically distinct cell types to form the human organism. The DNA methylation profile defines tissue identity[3] and is largely conserved over a lifetime, specific changes occur as life progresses.[4] In addition, external stimuli, such as lifestyle and environment, are capable of introducing DNA methylation alterations associated with phenotypic changes, including disease susceptibility.[5] aberrant DNA methylation has been reported for diverse diseases, with cancer being associated with the most profound changes.[6] Specific DNA methylation changes and genome-wide alterations are involved in all steps of tumorigenesis.[7] In particular, the epigenetic silencing of tumor-suppressor genes (TSGs) is generally thought to be of great importance to cancer onset and to driving tumorigenesis
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