Abstract ED02-01: Epigenetic variation as the missing link between aging and cancer

Abstract

Abstract DNA methylation affects gene expression and genome stability in complex ways depending on the location of the CpG site in question. In humans, methylation patterns are highly regulated and generally conserved between different individuals with R2>0.98 when comparing promoter DNA methylation genome wide among unrelated individuals of similar age. Despite this high degree of regulation, there are quantitative differences in methylation between individuals as well as evidence of methylation drift (increase at some loci, decrease at other loci) associated with aging in mammals. There is also a large degree of methylation drift in cancer cells (compared to normal tissues in the same individual) and a smaller but significant drift in other diseases such as atherosclerosis and neuro-degeneration. Genome wide methylation drift associated with age in multiple species (humans, mice, monkeys) is tissue specific and affects up to a quarter of the methylome. The consequences of drift are twofold. First, it induces epigenetic diversity within a tissue that can serve as fodder for Darwinian selection to promote the development of proliferative diseases such as cancer and atherosclerosis. Second, given that some genes are affected more prominently due to genomic structural features, enough cells are affected in older tissues to potentially change gene expression and tissue function. The determinants of age-related methylation drift remain largely unknown. There are diverse observations suggesting that the rate of drift can be modified by diet, chronic inflammation and exposures, and preliminary data suggesting a genetic component to the drift as well. Some of the outstanding questions in the field include the possibilities that methylation drift is modified by germline polymorphisms that influence DNA methylation genome wide, by prenatal exposures including diet and environmental toxins, and by lifestyle factors (including diet, exposures and exercise) that affect low level inflammation systemically. The model whereby methylation drift enables Darwinian selection at the tissue level also implies that possibility of preventing age-related development of pre-neoplasia and neoplasia through interventions targeting epigenetic processes. Citation Format: Jean-Pierre Issa. Epigenetic variation as the missing link between aging and cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED02-01.