Aging, methylation and cancer.
Alterations in methylation are widespread in cancers. DNA methylation of promoter-associated CpG islands is an alternate mechanism to mutation in silencing gene function, and affects tumor-suppressor genes such as p16 and RBI, growth and differentiation controlling genes such as ER and many others. Evidence is now accumulating that some of these methylation changes may initiate in subpopulations of normal cells as a function of age and progressively increase during carcinogenesis. Age-related methylation appears to be widespread and is one of the earliest changes marking the risk for neoplasia. In colon cancer, we have shown a pattern of age-related methylation for several genes, including ER, IGF2, N33 and MyoD, which progresses to full methylation in adenomas and neoplasms. Hypermethylation of these genes is associated 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 cancers 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 causes of age-related methylation are still unknown at this point, but evidence points to an interplay between local predisposing factors in DNA (methylation centers), levels of gene expression and environmental exposure. The concept that age-related methylation is a predisposing factor for neoplasia implies that it may serve as a diagnostic risk marker in cancer, and as a novel target for chemoprevention. Studies in animal models support this hypothesis and should lead to novel approaches to risk-assessment and chemoprevention in humans.
Ahuja
N
N
The Johns Hopkins Oncology Center and Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, USA.
Issa
J P
JP
D000375:Aging / Q000235:genetics*; D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*
D004273:DNA, Neoplasm