Abstract
Although at the genetic level cancer is caused by diverse mutations, epigenetic modifications are characteristic of all cancers, from apparently normal precursor tissue to advanced metastatic disease, and these epigenetic modifications drive tumour cell heterogeneity. We propose a unifying model of cancer in which epigenetic dysregulation allows rapid selection for tumour cell survival at the expense of the host. Mechanisms involve both genetic mutations and epigenetic modifications that disrupt the function of genes that regulate the epigenome itself. Several exciting recent discoveries also point to a genome-scale disruption of the epigenome that involves large blocks of DNA hypomethylation, mutations of epigenetic modifier genes and alterations of heterochromatin in cancer (including large organized chromatin lysine modifications (LOCKs) and lamin-associated domains (LADs)), all of which increase epigenetic and gene expression plasticity. Our model suggests a new approach to cancer diagnosis and therapy that focuses on epigenetic dysregulation and has great potential for risk detection and chemoprevention.
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Acknowledgements
This work was supported by US National Institute of Health (NIH) grants CA05438 and HG03233 to A.P.F. The authors thank D. Singer, I. Ernberg and J. Bradner for helpful discussions.
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Glossary
- Bivalent modifications
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Nucleosomes containing both euchromatic histone H3 lysine 4 trimethylation (H3K4me3) and heterochromatic H3K27me3 post-translational modifications.
- Cancer hallmarks
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Ten biological properties of cancer that are said to define the disease; we argue that they arise by natural selection for cellular survival at the expense of the host in the setting of epigenetic dysregulation and random variation.
- Cancer-specific differentially methylated regions
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(cDMRs). Differentially methylated regions that distinguish cancer cells from normal cells.
- Chemoprevention
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Administration of pharmacological compounds to reduce cancer incidence without certain knowledge of its effect on a given patient.
- CpG islands
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(CGIs). Areas of high CpG dinucleotide density in the genome, typically defined as a region at least 200 bp long with >50% GC dinucleotides and an observed-to-expected CpG ratio of >0.6.
- CpG island shores
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(CGI shores). The region 2 kb on either side of a CpG island, and the location of most cancer-specific, tissue-specific and reprogramming-specific differentially methylated regions.
- Epigenetic dysregulation
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The loss of normal control of DNA methylation or chromatin as a result of injury, epigenetic change or mutation, leading to phenotypic drift.
- Epigenetic variability
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Increased inter-sample variation in the methylation or chromatin state. This was recently identified as a common property of cancer, allowing for more accurate detection between samples.
- Euchromatin
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Areas of the genome that are more open to transcription owing to post-translational modifications of histones and with less nucleosome density.
- Heterochromatin
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Areas of the genome that are less open to transcription owing to post-translational modifications of histones and with greater nucleosome density. Facultative heterochromatin can change between the two states. Large organized chromatin lysine modifications and lamina-associated domains describe heterochromatin over relatively large regions and are associated with the nuclear membrane.
- Hypomethylated blocks
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Large (mean 144 kb) regions that are broadly hypomethylated in cancer and that mostly overlap with large organized chromatin lysine modifications and lamina-associated domains.
- Lamina-associated domains
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(LADs). Genomic regions located in the nuclear periphery that are associated with lamina (an inner nuclear membrane-associated protein) and usually have low expression levels.
- Large organized chromatin lysine modifications
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(LOCKs). Large heterochromatic regions characterized by low gene expression that are altered between somatic and stem cells; they are typically lost in cancer cells.
- Loss of imprinting
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(LOI). Loss of parent of origin-specific expression in cancer of imprinted genes, first observed for insulin-like growth factor 2 (IGF2) in Wilms' tumour and colorectal cancer.
- Ornstein–Uhlenbeck process
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An overdamped Brownian harmonic oscillator — that is, stochastic variation from a normal state with no persistence of the rate of change — opposed by a stronger restoring force towards the equilibrium point. We are using this to model stochastic change in DNA methylation.
- Reprogramming-specific differentially methylated regions
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(rDMRs). Differentially methylated regions that distinguish reprogrammed stem cells from somatic cells.
- Tissue-specific differentially methylated regions
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(tDMRs). Differentially methylated regions that distinguish normal tissues from each other.
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Timp, W., Feinberg, A. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat Rev Cancer 13, 497–510 (2013). https://doi.org/10.1038/nrc3486
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DOI: https://doi.org/10.1038/nrc3486
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