DNA methylation abnormalities at gene promoters are extensive and variable in the elderly and phenocopy cancer cells.

Abnormal patterns of DNA methylation are one of the hallmarks of cancer cells. The process of aging has also been associated with similar, albeit less dramatic, changes in methylation patterns, leading to the hypothesis that age-related changes in DNA methylation may partially underlie the increased risk of cancer in the elderly. Here we studied 377 participants aged 85 yr from the Newcastle 85+ Study to investigate the extent of, and interindividual variation in, age-related changes in DNA methylation at specific CpG islands. Using highly quantitative pyrosequencing analysis, we found extensive and highly variable methylation of promoter-associated CpG islands with levels ranging from 4% to 35%, even at known tumor suppressor genes such as TWIST2. Furthermore, the interindividual differences in methylation seen across this elderly population phenocopies multiple features of the altered methylation patterns seen in cancer cells. Both aging- and cancer-related methylation can occur at similar sets of genes, both result in the formation of densely methylated, and likely transcriptionally repressed, alleles, and both exhibit coordinate methylation across multiple loci. In addition, high methylation levels were associated with subsequent diagnosis of leukemia or lymphoma during a 3-yr follow-up period (P=0.00008). These data suggest that the accumulation of age-related changes in promoter-associated CpG islands may contribute to the increased cancer risk seen during aging.-Gautrey, H. E., van Otterdijk, S. D., Cordell, H. J., Newcastle 85+ study core team, Mathers, J. C., Strathdee, G. DNA methylation abnormalities at gene promoters are extensive and variable in the elderly and phenocopy cancer cells.