Journal Article

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

Koldobskiy, Michael A., Feinberg, Andrew P., Göndör, Anita

2016

Overview

Key Points The functional classification system introduced here divides the genes that shape the cancer epigenome into three categories: epigenetic modifiers that directly modify the cancer epigenome and are frequent targets of mutations and epimutations; epigenetic mediators that drive the tumour or its progenitor cells towards a more stem-like state; and epigenetic modulators that transmit environmental signals to epigenetic modifiers. Epigenetic mediator-induced epigenetic variation in the cells of origin might lead to increased phenotypic flexibility and heterogeneity long before the emergence of oncogenic mutations and is subsequently selected in the tumour tissue during progression. Sites of increased epigenetic variation in precancerous lesions and cancer localize to large domains, called hypomethylated blocks, that overlap with regions of repressive chromatin modifications acquired during development (large organized chromatin K9 modifications) and are particularly sensitive to ageing and cancer-predisposing environmental signals. Increased epigenetic variation is a predictor of cancer risk and cancer progression; it promotes the adaptation of the tumour tissue to changing environmental cues by continuously re-establishing tumour cell phenotypic heterogeneity. The mechanism of increased epigenetic variation is functionally intertwined with the perturbations of the 3D genome organization and the disruption of heterochromatin compartments within the nuclear architecture. Disruption to the epigenome is increasingly appreciated as a major contributor to the development of cancer. The authors discuss how conceptualizing genes affecting the epigenome as epigenetic modulators, epigenetic modifiers or epigenetic mediators provides a valuable framework for understanding diverse aspects of the causes and consequences of epigenome alteration in cancer. This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of 'tumour progenitor genes'. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: 'epigenetic mediators', corresponding to the tumour progenitor genes suggested earlier; 'epigenetic modifiers' of the mediators, which are frequently mutated in cancer; and 'epigenetic modulators' upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/212/177 / 631/208/2489/2487 / 631/208/68 / 631/208/68/2486 / 631/337/100 / Agriculture / Animal Genetics and Genomics / Animals / Biomedicine / Cancer Research / Carcinogenesis / Disease Progression / Disease susceptibility / DNA Methylation / Epigenesis, Genetic / Gene Function / Gene mutations / Genes / Genetic aspects / Health aspects / Human Genetics / Humans / Identification and classification / Mutation - genetics / Neoplasms - etiology / Neoplasms - pathology / Properties / review-article / Stem Cells - pathology