title: Low colonocyte folate is associated with uracil misincorporation and global DNA hypomethylation in human colorectum.
abstract: 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 ± CI) from the site distal to the polyp (16.9 ± 2.4), to the site adjacent to the polyp (14.7 ± 2.3), to the polyp (12.8 ± 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 μg/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.
authors.affiliation: Centre for Molecular Biosciences, University of Ulster, Coleraine, Northern Ireland.
authors.forename: Angela P
authors.initials: AP
authors.lastname: McGlynn
authors.forename: Gillian R
authors.initials: GR
authors.lastname: Wasson
authors.forename: Sharleen L
authors.initials: SL
authors.lastname: O'Reilly
authors.forename: Helene
authors.initials: H
authors.lastname: McNulty
authors.forename: C Stephen
authors.initials: CS
authors.lastname: Downes
authors.forename: Chin-Kuo
authors.initials: CK
authors.lastname: Chang
authors.forename: Leane
authors.initials: L
authors.lastname: Hoey
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.forename: Mary
authors.initials: M
authors.lastname: Ward
authors.forename: J J
authors.initials: JJ
authors.lastname: Strain
authors.forename: George
authors.initials: G
authors.lastname: McKerr
authors.forename: Donald G
authors.initials: DG
authors.lastname: Weir
authors.forename: John M
authors.initials: JM
authors.lastname: Scott
mesh_terms: D018256:Adenomatous Polyps / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D020137:Base Pair Mismatch; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003111:Colonic Polyps / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D019175:DNA Methylation; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006965:Hyperplasia; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity; D012007:Rectum / Q000378:metabolism / Q000473:pathology; D014498:Uracil / Q000378:metabolism
chemical_list: D015415:Biomarkers; D014498:Uracil; D004247:DNA; D005492:Folic Acid