Aging, methylation and cancer

Alterations in methylation are widespread in cancers. DNA methylation of pr omoter-associated CpG islands is an alternate mechanism to mutation in sile ncing gene function, and affects tumor-suppressor genes such as p16 and RB1 , growth and differentiation controlling genes such as ER and many others. Evidence is now accumulating that some of these methylation changes may ini tiate in subpopulations of normal cells as a function of age and progressiv ely increase during carcinogenesis. Age-related methylation appears to be w idespread and is one of the earliest changes marking the risk far neoplasia . In colon cancer, we have shown a pattern of age-related methylation for s everal genes, including ER, IGF2, N33 and MyoD, which progresses to full me thylation in adenomas and neoplasms. Hypermethylation of these genes is ass ociated with gene silencing. Age-related methylation involves at least 50% of the genes which are hypermethylated in colon cancer, and we propose that such age-related methylation may partly account for the fact that most can cers occur as a function of old age. Age-related methylation, then, may be a fundamental mark of the field defect in patients with neoplasia. The caus es of age-related methylation are still unknown at this point, but evidence points to an interplay between local predisposing factors in DNA (methylat ion centers), levels of gene expression and environmental exposure. The con cept that age-related methylation is a predisposing factor for neoplasia im plies that it may serve as a diagnostic risk marker in cancer, and as a nov el target for chemoprevention. Studies in animal models support this hypoth esis and should lead to novel approaches to risk-assessment and chemopreven tion in humans.