Department of Biochemistry and Molecular Biology, University of Southern California School of Medicine, The Norris Comprehensive Cancer Center, Los Angeles 90033, USA. jones_p@froggy.hsc.usc.edu
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.