Elsevier

Seminars in Cancer Biology

Volume 14, Issue 6, December 2004, Pages 427-432
Seminars in Cancer Biology

The epigenetics of cancer etiology

https://doi.org/10.1016/j.semcancer.2004.06.005Get rights and content

Abstract

Epigenetic dysregulation is central to cancer development and progression. This dysregulation includes hypomethylation leading to oncogene activation and chromosomal instability, hypermethylation and tumor suppressor gene silencing, and chromatin modification acting directly, and cooperatively with methylation changes, to modify gene expression. In addition, disrupted genomic imprinting appears to contribute to colorectal cancer risk, and serves as a gatekeeper in Wilms tumor. A cancer predisposing disorder, Beckwith–Wiedemann syndrome, usually arises from epigenetic errors, solidifying the causal role of epigenetics in cancer. While cancer epigenetics has been reviewed extensively elsewhere, the main focus of this review will be to present the view that epigenetics and genetics are complementary in the area of cancer etiology, the focus of this volume. I propose a hypothesis in which epigenetic alterations contribute to tumor progression, but they also increase the probability that genetic changes, when they occur, will lead to cancer initiation. This hypothesis could contribute to a new understanding of the role of environmental carcinogens that may not be fully explained through a purely genetic view or by tests, such as bacterial mutation frequency, that ignore epigenetic factors.

Section snippets

Background

The field of cancer epigenetics has been reviewed extensively by me and others, and I therefore do not wish to repeat much of that here, but refer to prior publications [1], [2], [3]. Rather, the purpose of this article is to discuss a topic that has not received as much attention, namely the potential relationship of cancer epigenetics to cancer etiology, the subject of this volume, and particularly its relationship to conventional genetic changes. For example, Where do epigenetic changes fit

Comparison of the genetic and epigenetic models of cancer

I emphasize that the epigenetic model of cancer does not contradict the genetic model; the epigenetic model complements the genetic model. That said, I will contrast the two. The genetic model of cancer states that cancer is caused by mutations in genes. One therefore investigates cancer mechanism by a search for mutations, deletions, rearrangements, and gene amplification. The genetic model appears to explain most rare cancer family syndromes. It also appears correct for cancer initiation,

Environmental impact on epigenetics

The role of the environment, and carcinogens in particular in causing epigenetic changes, has not received a great deal of attention, yet it is a relatively old idea. Poirier showed over 20 years ago that alteration in dietary methylation, specifically methyl depletion with low choline and methionine, leads to spontaneous liver cancers in rats. More recently, hypomethylation of the MDR1 gene has been linked to increased drug resistance in acute myelogenous leukemia [38]. Cadmium inhibits the

An epigenetic hypothesis of carcinogenesis

Here I would like to explore where epigenetic changes might fit into carcinogenic mechanisms, particularly those related to environmental changes and the action of carcinogens. The epigenetic hypothesis of cancer states that epigenetic modification can serve in two critical roles, in cancer initiation and in cancer progression. In cancer initiation, genetic and epigenetic alterations may interact in that epigenetic alterations may determine the effect of subsequent genetic insults. Even

Conclusion

The epigenetic model of cancer, which is complementary to the genetic model, can help to explain the action of environmental carcinogens, as well as tumor progression. Epigenetic dysregulation can help to explain activation of genes that promote tumor invasion and metastasis as well as activation of latent viral oncogenes and silencing of tumor suppressor genes. The epigenetic model can also help to explain common cancer risk, as a common epigenetic variant in IGF2 imprinting is associated with

Acknowledgements

I thank George Klein and Michele Carbone for stimulating discussion, and Hengmi Cui and Patrick Onyango for comments. This work was supported by NIH Grant CA65145.

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