title: Defining, distinguishing and detecting the contribution of heterogeneous methylation to cancer heterogeneity.
abstract: DNA methylation is a fundamental means of epigenetic gene regulation that occurs in virtually all cell types. In many higher organisms, including humans, it plays vital roles in cell differentiation and homeostatic maintenance of cell phenotype. The control of DNA methylation has traditionally been attributed to a highly coordinated, linear process, whose dysregulation has been associated with numerous pathologies including cancer, where it occurs early in, and even prior to, the development of neoplastic tissues. Recent experimental evidence has demonstrated that, contrary to prevailing paradigms, methylation patterns are actually maintained through inexact, dynamic processes. These processes normally result in minor stochastic differences between cells that accumulate with age. However, various factors, including cancer itself, can lead to substantial differences in intercellular methylation patterns, viz. methylation heterogeneity. Advancements in molecular biology techniques are just now beginning to allow insight into how this heterogeneity contributes to clonal evolution and overall cancer heterogeneity. In the current review, we begin by presenting a didactic overview of how the basal bimodal methylome is established and maintained. We then provide a synopsis of some of the factors that lead to the accrual of heterogeneous methylation and how this heterogeneity may lead to gene silencing and impact the development of cancerous phenotypes. Lastly, we highlight currently available methylation assessment techniques and discuss their suitability to the study of heterogeneous methylation.
authors: Johns Hopkins Institute for NanoBioTechnology, Baltimore, MD 21218, USA.
authors: Thomas R
authors: TR
authors: Pisanic
authors: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
authors: Pornpat
authors: P
authors: Athamanolap
authors: Johns Hopkins Institute for NanoBioTechnology, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Cancer Biology Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA; Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. Electronic address: thwang@jhu.edu.
authors: Tza-Huei
authors: TH
authors: Wang
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000235:genetics*; D018740:Genetic Heterogeneity; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D013269:Stochastic Processes
keywords: Cancer; DNA methylation; Epigenetics; Molecular diagnostics; Tumor heterogeneity