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. 2013 Mar 28;153(1):38-55.
doi: 10.1016/j.cell.2013.03.008.

Interplay Between the Cancer Genome and Epigenome

Free PMC article

Interplay Between the Cancer Genome and Epigenome

Hui Shen et al. Cell. .
Free PMC article


Cancer arises as a consequence of cumulative disruptions to cellular growth control with Darwinian selection for those heritable changes that provide the greatest clonal advantage. These traits can be acquired and stably maintained by either genetic or epigenetic means. Here, we explore the ways in which alterations in the genome and epigenome influence each other and cooperate to promote oncogenic transformation. Disruption of epigenomic control is pervasive in malignancy and can be classified as an enabling characteristic of cancer cells, akin to genome instability and mutation.


Figure 1
Figure 1. Representative Epigenetic States
Examples of representative epigenetic states are shown for several typical categories of genes and in different cellular contexts. A. CpG-poor promoters are often tissue-specific and/or reside in inducible genes which can be readily turned on or off. Transcription factor (TF) binding at regulatory elements and the promoter initiates nuclear depleted regions (NDR). B. Many genes with CpG island promoters are constitutively expressed housekeeping genes. C. Some genes with CpG island promoters, such as transcription factor master regulators of differentiation and development are repressed by the Polycomb complexes in stem cells and kept in a bivalent state with both active and repressive marks. D. Polycomb targets in stem cells are predisposed to cancer-specific promoter hypermethylation.
Figure 2
Figure 2. Histone H3 Lysine Writers, Erasers and Readers
Although many other important histone modifications also occur, only major histone H3 lysine modifications (Ac: Acetylation; me1: monomethylation; me3: trimethylation) with well-defined functions are shown above a representative gene. The distribution of the marks are shown as colored bars and wedges to indicate approximate abundance. Repressive marks are shown in red, and active marks in blue. Epigenetic regulators are listed to the right of each mark. Acetylation across different lysines share writers and erasers, while methylation usually has dedicated enzymes. Readers (which can also be writers and erasers themselves) recognize different chromatin states and propagate the signal in various ways, including self reinforcement or cross talk, transcriptional activation or repression, or DNA repair. Crosstalk can also occur between histone modification and DNA methylation, since DNMT3A, DNMT3L, UHRF1 all contain reader domains for chromatin states.
Figure 3
Figure 3. Genetic Alterations in Epigenetic Regulators
Mutations and other genetic alterations reported for selected epigenetic regulators are shown for various types of human cancer in a heatmap. Malignancies are grouped by epithelial, hematological and other cancers. Mutations, represented by colored cells, are deemed loss of function (blue) unless evidence for gain of function (either hypermorphic or neomorphic, red) has been shown. Other genetic alterations are plotted with different symbols, with a slash indicating translocation events and a dot indicating copy number alterations. Translocations that generate oncogenic fusion proteins are represented in red as well. The mutation frequencies, represented by the darkness of the shade, are based on recent whole genome-exome studies, with adjustments made where whole-genome/exome studies are not available or have a small sample size. Different subtypes of lung cancers are combined without adjusting for subtype prevalence and certain mutations may only represent one subtype. Cells showing no entry may represent false negatives in our curation or in the literature, and cancer types highly covered with whole-genome/exome studies (e.g. breast cancer) might have fewer false negatives than those that are not. MSS/MSI – microsatellite stable/instable (MSI CRCs are excluded due to the high background mutation rate); DLBCL - Diffuse large B-cell lymphoma; FL – follicular lymphoma.
Figure 4
Figure 4. Genetic Disruption of Epigenetic Control at H3K27 in Cancer
The counteracting writer EZH2 and eraser KDM6A/UTX form a pair in regulating an important epigenetic mark, methylation at H3 lysine 27. EZH2 catalyzes the methylation process with help from other components in the Polycomb Repressive Complex 2 (PRC2), while KDM6A, part of the Trithorax complex, removes this repressive mark. The K27me3 mark attracts another Polycomb complex, PRC1, which ubiquitinates H2AK119, and thereby blocks PolII elongation. Another Polycomb complex, PR-DUB is also critical to the maintainance of the repression at a subset of the Polycomb genes, although it removes the H2AK119ub mark and thus counteracts PRC1 in that regard. Mutations and genetic alterations spanning a wide spectrum of human cancers hit this epigenetic pathway. Solid tumors show possibly neomorphic histone K27 mutations (mimicking H3K27me2), UTX mutation, EZH2 amplification and/or overexpression due to genomic loss of the repressive microRNA miR101, as well as amplification/overexpression of the PRC1 member BMI1, and lymphoma exhibits gain-of-function mutations of EZH2, consistent with a gain of Polycomb repression (red boxes) in the affected malignancies. In contrast, myeloid malignancies and ALL, particularly early T-cell precursor ALL show mutations that could sabotage Polycomb repression (blue boxes). Mouse models show that loss of BAP1, the enzymatic unit of PR-DUB, leads to myeloid transformation, although BAP1 mutation in MDS is rare. Gray boxes indicate that the effect on H3K27me3 is not clear.
Figure 5
Figure 5. Interplay Between the Cancer Genome and Epigenome
The genome and epigenome influence each other, as the genome provides the primary sequence information and encodes regulators of epigenetic states, while the epigenome controls the accessibility and interpretation of the genome. Changes in one can influence the other, forming a partnership in producing genetically or epigenetically encoded phenotypic variation subject to Darwinian selection for growth advantage, and thus eventually achieving the hallmarks of cancer (Hanahan and Weinberg, 2011). Genetic instability and mutation, and epigenomic disruption can be considered enabling characteristics of cancer cells.

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