• Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS 8110, MSC 7240, Bethesda, MD 20892, USA. huangw@mail.nih.gov

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.

IMPACT: Adequate folate status may protect against colorectal carcinogenesis through mechanisms involving adequate DNA methylation in the genome.