Introduction: Cancer as an Epigenetic Disease
The term “epigenetic” was coined to describe the phenomenon of cell identity3; the human body has more than 200 different cell types all dependent on a single genome. This diversity in cellular identities is governed by a network of biochemical modifications to DNA and to the histone proteins that provide structure to DNA. Altogether, these modifications are referred to as the epigenome. Medically, things became even more interesting when it was discovered that variation in the epigenome could also be responsible for phenotypic variation,4 for example, coat color or susceptibility to obesity in mouse models. There is intense interest currently in decoding the epigenome and relating this code to varied phenotypes and diseases in humans.
That cancer has an epigenetic component is obvious.2 Cancer cells have profound defects in cellular identity (most evident by morphology and differentiation states), and the cancer epigenome is very different than the epigenome of normal cells. It has been assumed that these changes are a consequence of genetic damage rather than a cause of neoplastic transformation, but this assumption turns out to be (often) incorrect. It was demonstrated decades ago that reprogramming the cancer epigenome by forcing cells to undergo embryogenesis can reverse the transformed phenotype.5,6 These experiments have been reproduced by modern reprogramming technology such as nuclear transfer or iPS protocols.7,8 These experiments showed that the cancer phenotype cannot be attributed solely to the genetic damage (that persisted through the reprogramming procedures). Furthermore, large-scale sequencing studies and laboratory confirmation have shown that cancer-causing genetic damage frequently affects proteins involved in writing, erasing, or reading the epigenetic code,9 demonstrating that epigenetic “errors” are the causative elements in explaining the ultimate cancer phenotype.
Final confirmation of cancer as an epigenetic disease came from 5 observations that recapitulate the evidence for a genetic etiology of cancer described earlier: (i) Familial cancer can also be due to constitutional epigenetic damage (“epimutations”)10; (ii) cancer cells carry a considerable load of epigenetic damage,9 sometimes with no discernible recurrent genetic damage11; (iii) epigenetic instability (e.g., the CpG island methylator phenotype) is a feature of many cancers12; (iv) introducing epimutations is sufficient to promote neoplasia in mice13 and (iv) carcinogens are often also epimutagens.14
What are the translational implications of an epigenetic etiology of cancer? Just like genetic damage, epimutations could be useful as biomarkers for risk assessment, diagnosis, prognosis, and treatment selection (precision medicine). In fact, in distinct cases, epimutations appear to perform better than mutations for these tasks, and it seems unavoidable that epigenetic profiles will be incorporated into the clinicopathologic assessments of neoplasia.15 Clinically, the field of epigenetic biomarkers is poised for rapid expansion in the future. Therapeutically, there are 2 major differences between genetic damage and epigenetic damage. Genetic activation of oncogene function has provided a very successful strategy for targeting cancer cells, and it is unclear whether epigenetic activation of oncogenes provides a similar opportunity. On the other hand, epigenetic damage can be reversed by targeting the writers/erasers/readers of the epigenetic code in a way that cannot be done for genetic damage.