DNA hypermethylation: when tumour suppressor genes go silent

The phenotype of the cancerous cell may arise either from genetic alterations that disrupt gene function through sequence modifications (mutations) or epigenetic events that may alter the heritable state of gene expression (i.e. without changing the actual sequence of the genome). Whereas mutations in certain tumour suppressor genes are most often thought of in association with their inactivation during cancer initiation or progression, epigenetic alterations such as DNA methylation appear to be tightly linked to the sequential non-reversible events of normal tissue differentiation and organogenesis. This highlights a link between tissue differentiation and tumourigenesis with respect to the stable nature of certain epigenetic changes. In the case of tumourigenesis, both genetic and epigenetic mechanisms of altered gene expression often go hand in hand; not surprisingly, biallelic inactivation of a given tumour suppressor gene may occur via a combination of mutational and epigenetic events and is entirely consistent with the Knudson two-hit hypothesis of tumourigenesis. This review summarizes recent developments within the field of DNA methylation, highlighting its association with the transcriptional silencing of tumour suppressor genes in a variety of human cancers.