Age-associated changes in promoter CpG island methylation and their potential role in cancer development

Abstract

Changes in DNA methylation patterns are a hallmark of both cancer and ageing, and may underlie susceptibility to developing age-related diseases such as cancer. To uncover the impact that such variation has on health and ageing, we assessed DNA methylation patterns in the peripheral blood leukocytes (PBL) of 480 participants in the Newcastle 85+ study to determine the levels, and degree of inter-individual variation, of DNA methylation in the promoter region of a panel of genes by Pyrosequencing. We found considerable inter-individual variation in promoter CpG methylation in several genes and a remarkable similarity to leukaemic patterns of aberrant methylation. This included specific methylation of the same sets of genes, strong correlations between methylation of the genes (in a pattern reminiscent of the CpG island methylator phenotype observed in cancer) and the presence of densely methylated alleles in highly methylated individuals, identical to patterns observed in cancer cells. This suggests that ageing and cancer related methylation may be closely linked. Further analysis of PBL DNA methylation levels in Newcastle 85+ study participants with a previous history of cancer (n=113) versus cancer-free individuals (n=113) found significantly higher methylation in those with a cancer history (10.71% vs. 10.21%, p=0.04). Further, a separate group of 72 individuals diagnosed with cancer within the 3 year duration of the study had similarly increased methylation levels (10.96% vs. 10.36%, p=0.03), suggesting that pre-existing methylation in normal cells may increase risk of cancer and may be evident prior to clinically detectable disease. In addition, individuals with increased DNA methylation were more likely to be categorised as frail (as defined by Fried) than those with lower DNA methylation measures, indicating that disrupted methylation patterns are associated with detrimental effects on healthy ageing. Subsequently, a GWAS analysis found that SNPs in two genes, DSCAM and DSCAML1, appeared to be associated with determining DNA methylation levels in the Newcastle 85+ study participants.