Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the Normative Aging Study
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Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case–control studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case–control studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear.
In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing.
Individuals with low LINE-1 methylation (<median) had a 3.0-fold (95%CI 1.3–6.9) increased incidence of all cancers combined. LINE-1 and Alu methylation were not significantly associated with cancer prevalence at baseline (all cancers combined). However, individuals with low LINE-1 methylation (<median) had a 3.2-fold (95% CI 1.4–7.5) higher prevalence of lung cancer. Individuals with low LINE-1 or Alu methylation (<median) had increased cancer mortality (HR = 3.2, 95%CI 1.3–7.9 for LINE-1; HR = 2.5, 95%CI 1.1–5.8 for Alu).
These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer.
KeywordsRepetitive elements DNA methylation Epigenetics Blood Cancer risk
This work was supported by National Institute of Environmental Health Sciences grants ES015172-01; New Investigator funding from the HSPH-NIEHS Center for Environmental Health (ES000002); Environmental Protection Agency grants R83241601 and R827353; and Italian Association for Cancer Research (AIRC-6016). The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC).
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