title: Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the Normative Aging Study.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer.
authors.affiliation: Center of Molecular and Genetic Epidemiology, Department of Environmental and Occupational Health, Università degli Studi di Milano and IRCCS Maggiore Policlinico Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy.
authors.forename: Zhong-Zheng
authors.initials: ZZ
authors.lastname: Zhu
authors.forename: David
authors.initials: D
authors.lastname: Sparrow
authors.forename: Lifang
authors.initials: L
authors.lastname: Hou
authors.forename: Letizia
authors.initials: L
authors.lastname: Tarantini
authors.forename: Valentina
authors.initials: V
authors.lastname: Bollati
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.forename: Antonella
authors.initials: A
authors.lastname: Zanobetti
authors.forename: Pantel
authors.initials: P
authors.lastname: Vokonas
authors.forename: Robert O
authors.initials: RO
authors.lastname: Wright
authors.forename: Andrea
authors.initials: A
authors.lastname: Baccarelli
authors.forename: Joel
authors.initials: J
authors.lastname: Schwartz
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D019175:DNA Methylation; D006801:Humans; D015994:Incidence; D007962:Leukocytes / Q000737:chemistry*; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D015995:Prevalence; D012091:Repetitive Sequences, Nucleic Acid