Pan-cancer patterns of DNA methylation

Abstract

The comparison of DNA methylation patterns across cancer types (pan-cancer methylome analyses) has revealed distinct subgroups of tumors that share similar methylation patterns. Integration of these data with the wealth of information derived from cancer genome profiling studies performed by large international consortia has provided novel insights into the cellular aberrations that contribute to cancer development. There is evidence that genetic mutations in epigenetic regulators (such as DNMT3, IDH1/2 or H3.3) mediate or contribute to these patterns, although a unifying molecular mechanism underlying the global alterations of DNA methylation has largely been elusive. Knowledge gained from pan-cancer methylome analyses will aid the development of diagnostic and prognostic biomarkers, improve patient stratification and the discovery of novel druggable targets for therapy, and will generate hypotheses for innovative clinical trial designs based on methylation subgroups rather than on cancer subtypes. In this review, we discuss recent advances in the global profiling of tumor genomes for aberrant DNA methylation and the integration of these data with cancer genome profiling data, highlight potential mechanisms leading to different methylation subgroups, and show how this information can be used in basic research and for translational applications. A remaining challenge is to experimentally prove the functional link between observed pan-cancer methylation patterns, the associated genetic aberrations, and their relevance for the development of cancer.

Global delay in nascent strand DNA methylation

“…In our DKO experiments we made the intriguing observation that reduced global methylation levels appear to increase the nascent strand methylation rate. In the future, it will be interesting to further explore how substrate (hemi-methylated targets) and enzyme (DNMT1) levels affect the kinetics of post-replication methylation and whether this enzyme to substrate ratio can be mechanistically linked to the reduced, but generally stable, levels of global methylation across cancer types 32–34 . In this context, we show that intermediate methylation in cancer cells arises as a result of both inherent intercellular epigenetic heterogeneity and cell cycle linked heterogeneity.…”

The role of enhancers in cancer

“…Tumour cells often display either global hypomethylation or global hypermethylation compared with the respective normal cell types (reviewed in REFS 115,122). Although in many cases the mechanisms behind these methylation patterns are unclear, some specific somatic mutations that result in a global methyl ation phenotype have been identified.…”

Pan-cancer methylation and expression profiling of adenocarcinomas revealed epigenetic silencing in the WNT signaling pathway

“…However, relatively few studies have investigated methylation at a pan-cancer level. By reviewing methylomes across cancer types from singletumor-type studies, Witte et al [6] pinpointed some shared and distinct methylation signatures between cancer types.…”