Methylation mechanisms in pituitary tumorigenesis

Methylation is essential for embryonic development, however aberrant methyl ation of CpG islands associated with the tumour suppressor genes (TSGs) and leading to gene silencing is found in numerous tumour types. The TSG p16/C DKN2A is involved in the genesis of many tumour types and frequent methylat ion of the CpG island of the p16/CDKN2A gene is associated with loss of pro tein expression in pituitary tumours. In addition, CpG sites are mutational hotspots and abnormal methylation patterns have been shown to lead to gene tic instability, predisposing to, and preceding allelic loss. Although seve ral studies of pituitary tumours have shown loss of genetic material at kno wn and putative TSGs loci, studies of the retained alleles have revealed in frequent mutation, Equally, for several other TSGs no mechanisms have been described for their reduced expression. Methylation may represent a unifyin g theme, responsible in some cases for an absence or reduced expression and in other cases predisposing to allelic loss that may or may not encompass a TSG, In several tumour types treatment of tumours or their cognate cell l ines with demethylating agents induces expression of previously methylated genes. Using the mouse corticotroph cell line AtT20 as a model system, tran sfection studies showed restoration of growth control through induction of ectopically expressed p16/CDKN2A. These effects were reversed by prior in v itro methylation of the constructs' CpG sites within the coding region of t his gene. Methylation of an otherwise unmethylated CpG island renders a gen e transcriptionally incompetent and clinically these genes represent attrac tive therapeutic targets since the gene is neither lost nor mutated, but ma y be reactivated. Future studies will no doubt describe more efficacious ph armacological interventions and identify the mechanisms responsible for the abnormal methylation patterns seen in tumours including those of pituitary origin.