DNA methylation, epimutations and cancer predisposition.

Hereditary cancer syndromes caused by germline mutations give rise to distinct spectra of cancers with characteristic clinico-pathological features. Many of these hereditary cancer genes are silenced by methylation in a similar spectrum of sporadic cancers. It is likely that the initiating event in some of those cases of sporadic cancer is the somatic epigenetic inactivation (epimutation) of the same hereditary cancer gene. Recently, it has been shown that epimutations of certain hereditary cancer genes can be constitutional i.e. present throughout the soma. These epimutations may be inherited or arise very early in the germline. The heritability of these epimutations is very low as in most cases they are erased by passage through the germline. In other cases, predisposition to epimutations rather than the epimutations themselves can be inherited. These cases are characterised by Mendelian inheritance and are likely to be associated with sequence variants. Other sequence variants and environmental influences may also affect methylation propensity at a global level.