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Cancer-epigenetics comes of age

Abstract

The discovery of numerous hypermethylated promoters of tumour–suppressor genes, along with a better understanding of gene–silencing mechanisms, has moved DNA methylation from obscurity to recognition as an alternative mechanism of tumour–suppressor inactivation in cancer. Epigenetic events can also facilitate genetic damage, as illustrated by the increased mutagenicity of 5–methylcytosine and the silencing of the MLH1 mismatch repair gene by DNA methylation in colorectal tumours. We review here current mechanistic understanding of the role of DNA methylation in malignant transformation, and suggest Knudson's two–hit hypothesis should now be expanded to include epigenetic mechanisms of gene inactivation.

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Figure 1: Mechanism of transcriptional repression by DNA methylation.
Figure 2: Knudson's two–hit hypothesis revised.

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Acknowledgements

This work was supported by NIH/NCI grants R35 CA 49758 (P.A.J.) and R01 CA 75090 (P.W.L.)

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Jones, P., Laird, P. Cancer-epigenetics comes of age. Nat Genet 21, 163–167 (1999). https://doi.org/10.1038/5947

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