Cancer epigenetics comes of age

The discovery of numerous hypermethylated promoters of tumour-suppressor ge nes, along with a better understanding of gene-silencing mechanisms, has mo ved DNA methylation from obscurity to recognition as an alternative mechani sm 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 under standing of the role of DNA methylation in malignant transformation, and su ggest Knudson's two-hit hypothesis should now be expanded to include epigen etic mechanisms of gene inactivation.