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Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

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.

Abstract

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.

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Figure 1: Functional classification of cancer genes and their contribution to malignancy.
Figure 2: Change in cell state towards cancer stem cell states induced by reprogramming of the 3D epigenome.
Figure 3: Waddington landscape of phenotypic plasticity in development and cancer.

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Acknowledgements

The authors are grateful to R. Ohlsson for his valuable comments on the text and figures. The work discussed here was supported by the US National Institutes of Health grant CA54358 to A.F. and a grant from Karolinska Institutet to A.G.

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Correspondence to Andrew P. Feinberg.

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Competing interests

Under a licensing agreement between the Johns Hopkins University and Orion Genomics, A.P.F. is entitled to a share of royalty received by the university on technology related to the loss of imprinting described in this article, under terms managed by the Johns Hopkins University in accordance with its conflict of interest policies. M.A.K. and A.G. declare no competing interests.

PowerPoint slides

Glossary

Field effect

Epigenetic changes in a region of normal cells around a tumour.

CpG island methylator phenotype

The classification of cancers characterized by increased methylation at CpG-rich promoter regions, best characterized in colorectal cancer and glioma and associated with distinct histological and molecular features.

Epimutations

Abnormal epigenetic alterations leading to aberrant gene expression or silencing.

Cancer stem cells

(CSCs). A subpopulation of cancer cells with the ability to propagate the cancer cell population.

Loss of imprinting

(LOI). Loss of parent of origin-specific expression of imprinted genes in cancer.

Epigenetic stochasticity

Non-deterministic changes to epigenetic marks such as DNA methylation, giving rise to epigenetic variation that underlies cellular plasticity in both normal and pathological states, and that can be localized to specific genomic regions.

Canalization

The ability of an organism to produce a consistent developmental outcome despite variations in its environment.

Pleiotropic

Genetic or epigenetic changes that affect multiple seemingly unrelated phenotypic traits.

Non-linear dynamics

The behaviour of a system in which a small change in an input variable can induce a large change in the output. Modelling of chromatin structure and of the impact of chromatin states on transcription has demonstrated non-linear behaviour.

Waddington landscape

A metaphor of development, in which valleys and ridges illustrate the epigenetic landscape that guides a pluripotent cell to a well-defined differentiated state, represented by a ball rolling down the landscape.

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Feinberg, A., Koldobskiy, M. & Göndör, A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet 17, 284–299 (2016). https://doi.org/10.1038/nrg.2016.13

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