title: Prospective study of genomic hypomethylation of leukocyte DNA and colorectal cancer risk.
abstract: BACKGROUND
  Systematic genome-wide reductions of methylated cytosine (5-mC) levels have been observed in colorectal cancer tissue and are suspected to play a role in carcinogenesis, possibly as a consequence of inadequate folate intake. Reduced 5-mC levels in peripheral blood leukocytes have been associated with increased risk of colorectal cancer and adenoma in cross-sectional studies.
  
  
  METHODS
  To minimize disease- and/or treatment-related effects, we studied leukocyte 5-mC levels in prospectively collected blood specimens of 370 cases and 493 controls who were cancer-free at blood collection from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Leukocyte 5-mC level was determined by a high-pressure liquid chromatography (HPLC)/tandem mass spectrometry method and expressed as the relative amount of methyl to total cytosine residues, or %5-mC. We estimated the association between colorectal cancer risk and %5-mC categories by computing ORs and 95% confidence intervals (CI) through logistic regression modeling.
  
  
  RESULTS
  We observed no dose-dependent association between colorectal cancer and%5-mC categories (lowest vs. highest tertile: OR, 1.14; 95% CI, 0.80-1.63; P(trend) = 0.51). However, among subjects whose 5-mC levels were at the highest tertile, we observed an inverse association between natural folate intake and colorectal cancer (highest tertile of natural folate vs. lowest: OR, 0.35; 95% CI, 0.17-0.71; P(trend) = 0.003; P(interaction) = 0.003).
  
  
  CONCLUSIONS
  This prospective investigation show no clear association between leukocyte 5-mC level and subsequent colorectal cancer risk but a suggestive risk modification between 5-mC level and natural folate intake.
  
  
  CONCLUSIONS
  Adequate folate status may protect against colorectal carcinogenesis through mechanisms involving adequate DNA methylation in the genome.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS 8110, MSC 7240, Bethesda, MD 20892, USA. huangw@mail.nih.gov
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Huang
authors.forename: L Joseph
authors.initials: LJ
authors.lastname: Su
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Lee E
authors.initials: LE
authors.lastname: Moore
authors.forename: Hormuzd A
authors.initials: HA
authors.lastname: Katki
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Joel L
authors.initials: JL
authors.lastname: Weissfeld
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Yegnasubramanian
authors.forename: Mark P
authors.initials: MP
authors.lastname: Purdue
mesh_terms: D044503:5-Methylcytosine / Q000097:blood; D000368:Aged; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000097:blood* / Q000235:genetics*; D004247:DNA / Q000097:blood* / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005494:Folic Acid Deficiency / Q000097:blood / Q000235:genetics; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D011795:Surveys and Questionnaires
chemical_list: D044503:5-Methylcytosine; D004247:DNA