Prospective study of genomic hypomethylation of leukocyte DNA and colorectal cancer risk

Wen Yi Huang, L. Joseph Su, Richard B. Hayes, Lee E. Moore, Hormuzd A. Katki, Sonja I. Berndt, Joel L. Weissfeld, Srinivasan Yegnasubramanian, Mark P. Purdue

Research output: Contribution to journalArticlepeer-review

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; Ptrend = 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; Ptrend = 0.003; Pinteraction = 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 statusmayprotect against colorectal carcinogenesis through mechanisms involving adequate DNA methylation in the genome.

Original languageEnglish (US)
Pages (from-to)2014-2021
Number of pages8
JournalCancer Epidemiology Biomarkers and Prevention
Volume21
Issue number11
DOIs
StatePublished - Nov 2012

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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