Back in 2006, Andrew Feinberg & Co. brought forth a review that pioneered the concept of tumor progenitor genes, which are genes involved in stem cell reprogramming and cancer. These tumor progenitor genes are epigenetically deregulated at the earliest stage of cancer. The epigenetic variation occurs before mutations, can be seen in normal tissue surrounding the tumor, and ultimately results in altered differentiation. The gained epigenetic variation then acts together with subsequent mutations to drive tumor progression.
Now, to celebrate the decennial anniversary, the team is back at it again with more insights into the nature of tumor progenitor genes and two new classes of genes involved in the epigenetic plasticity that is critical to both cancer and development. We thought we’d take some time to highlight the key classification system in the new review.
Here’s how the new classification system works:
An Epigenetic Modulator is a gene that alters the activity of epigenetic machinery or provides additional layers of regulation. They are often involved in signalling pathways and are responsive to a changes in cellular environment that are caused by the external environmental exposures, age, inflammation, and/or other stresses. When an alteration occurs to an epigenetic modulator there is a change in the 3D nuclear architecture of normal cells, which makes it more likely that cancer will arise when a critical mutation occurs. Thus, mutations in them are optional and examples include IDH1/2, TP53, and CTCF.
An Epigenetic Modifier is a gene that modifies the epigenome or is involved in its interpretation. These genes typically modify the epigenome directly through DNA methylation, histone PTMs, and chromatin organization. In cancer, mutations are also optional and examples include DNMT3A, TET2, EZH2, and BRD4. Genomic sequence changes that alter the binding of regulators to chromatin, such as transcription factor binding sites and enhancers, are also included.
An Epigenetic Mediator is the updated term for a tumor progenitor gene, and represent genes targeted by epigenetic modifiers. Epigenetic mediators act to increase pluripotency or cell survival. In cancer, mutations are rare or absent and examples include OCT4, NANOG, and SOX2. They give tumours stem cell abilities, which ultimately results in the malignant state, and are a prime target for therapeutic intervention.
The Epigenetic Landscape of Cancer
Epigenetic modulators, modifiers, and mediators provide a modern synthesis of Waddington’s epigenetic landscape, which is a metaphor for cell development that now drives home the similarities of stem cell reprogramming and cancer. Aging, environmental exposures, and/or mutation alters epigenetic modulators that regulate the activity of epigenetic modifiers, which regulate the expression of epigenetic mediators. The ectopic expression of epigenetic mediators remodels the epigenetic landscape and creates a feedback loop with modulators and modifiers that alters the 3D nuclear architecture in the cell. All this remodelling ultimately results in a more stem cell like state that underlies cancer.
The EpiGene Verdict
Overall, this review offers a unique perspective and synthesis of the latest breakthroughs that tie together stem cell reprogramming and cancer. It provides a comprehensive overview of landmark studies to drive home the point that cancer should be reconsidered as a disease of the epigenome. The review is also complemented by a number of crisp graphics and informative tables that will help you keep your head above all the different layers that shape the epigenetic landscape of cancer.
The review appeals to a wide breadth of epigenetic researchers including those interested in cancer, development, and environmental exposure. Ultimately, it drives home the point that genetic mutation is not needed to start cancer and that cancers can be viewed as a disease of stem cell reprogramming.
Learn more about the similarities of cancer and stem cell differentiation in Nature Genetics, March 2016