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Low Colonocyte Folate Is Associated with Uracil Misincorporation and Global DNA Hypomethylation in Human Colorectum

McGlynn, Angela P, Wasson, Gillian R, O'Reilly, Sharleen R, McNulty, Helene, Downes, C. Stephen, Chang, Chin-Kuo, Hoey, Leane, Molloy, Anne M, Ward, Mary, Strain, JJ, McKerr, George, Weir, Donald G and Scott, John M (2013) Low Colonocyte Folate Is Associated with Uracil Misincorporation and Global DNA Hypomethylation in Human Colorectum. Journal of Nutrition, 143 . [Journal article]


DOI: 10.3945/jn.112.167148


Low folate status is a risk factor for colon carcinogenesis; mechanisms proposed to account for this relationship include uracil misincorporation into DNA and global DNA hypomethylation. We investigated whether such biomarkers are related to folate status in isolated colonocytes from colonoscopy patients. In cases with adenomatous polyps (n = 40) or hyperplastic polyps (n = 16), colonocytes were isolated from biopsies from the polyp, from a site adjacent to the polyp, and from normal mucosa 10–15 cm distal to the polyp. In polyp-free controls (n = 53), biopsies were taken from ascending, transverse, and descending areas of colon. Within adenoma cases, there was a trend (P-trend < 0.001) of decreasing colonocyte folate (pg/105 cells, mean 6 CI) from the site distal to the polyp (16.9 6 2.4), to the site adjacent to the polyp (14.7 6 2.3), to the polyp (12.8 6 2.0). Correspondingly, there were increases in uracil misincorporation (P-trend < 0.001) and global DNA hypomethylation (P-trend = 0.012) across the 3 sites. Colonocyte folate concentrations were significantly correlated with RBC folate concentrations, but only in individuals with generally lower (#484 mg/L) RBC folate status (r = 0.54; P = 0.006; n = 24), and were also significantly lower in normal mucosa of cases with adenomatous polyps than in controls matched for colonic segment. In conclusion, localized folate deficiency in specific areas of colon might create carcinogenic fields and affect the development of colorectal polyps through uracil misincorporation and DNA hypomethylation; alternatively, the polyp itself might deplete folate in the surrounding tissue. Folate supplementation trials aimed at colon cancer prevention should target individuals with suboptimal folate status.

Item Type:Journal article
Keywords:folate, colon cancer, DNA methylation, uracil misincorporation
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute > Genomic Medicine
Biomedical Sciences Research Institute > Northern Ireland Centre for Food and Health (NICHE)
Biomedical Sciences Research Institute
ID Code:24349
Deposited By: Professor Stephen Downes
Deposited On:18 Dec 2012 11:26
Last Modified:09 Dec 2015 11:09

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