title: Folic Acid Supplementation in Postpolypectomy Patients in a Randomized Controlled Trial Increases Tissue Folate Concentrations and Reduces Aberrant DNA Biomarkers in Colonic Tissues Adjacent to the Former Polyp Site.
abstract: Low folate status is associated with an increased risk of colorectal carcinogenesis. Optimal folate status may be genoprotective by preventing uracil misincorporation into DNA and DNA hypomethylation. Adenomatous polyps have low folate status compared with normal colonic mucosa, and they are surrounded by histologically normal mucosa that also is of low folate status.
  
  
  
  In a randomized controlled trial conducted at a single Dublin hospital between April 2002 and March 2004, we assessed the effect of folic acid supplementation on tissue folate, uracil misincorporation into DNA, and global DNA hypomethylation in colonocytes isolated from sites of adenomatous polyps and from histologically normal tissue adjacent and 10-15 cm distal to them.
  
  
  
  Twenty patients with adenomatous polyps on initial colonoscopy and polypectomy were randomly assigned to receive either 600 μg folic acid/d [n = 12, 38% men, mean age 64.3 y, and body mass index (BMI, in kg/m(2)) 26.6] or placebo (n = 8, 50% men, mean age 68.4 y, and BMI 27.2) for 6 mo, and then repeat the colonoscopy. Blood and colonocyte tissue folate concentrations were measured with the use of a microbiological assay. Uracil misincorporation and global DNA hypomethylation were measured in colonocytes with the use of modified comet assays.
  
  
  
  Over time, folic acid supplementation, compared with placebo, increased tissue folate (mean ± SEM) from 15.6 ± 2.62 pg/10(5) cells to 18.1 ± 2.12 pg/10(5) cells (P < 0.001) and decreased the global DNA hypomethylation ratio from 1.7 ± 0.1 to 1.0 ± 0.1 (P < 0.001). The uracil misincorporation ratio decreased by 0.5 ± 0.1 for the site adjacent to the polyp over time (P = 0.05).
  
  
  
  A response to folic acid supplementation, which increased colonocyte folate and improved folate-related DNA biomarkers of cancer risk, was seen in the participants studied. Exploratory analysis points toward the area formerly adjacent to polyps as possibly driving the response. That these areas persist after polypectomy in the absence of folate supplementation is consistent with a potentially carcinogenic field's causing the appearance of the polyp.
authors.affiliation: Departments of Biochemistry and Immunology and.
authors.forename: Sharleen L
authors.identifier: 0000-0003-3547-6634
authors.initials: SL
authors.lastname: O'Reilly
authors.affiliation: Northern Ireland Centre for Food & Health (NICHE), School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland; and.
authors.forename: Angela P
authors.initials: AP
authors.lastname: McGlynn
authors.affiliation: Northern Ireland Centre for Food & Health (NICHE), School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland; and.
authors.forename: Helene
authors.initials: H
authors.lastname: McNulty
authors.affiliation: Faculty of Health, Deakin University, Burwood, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: Northern Ireland Centre for Food & Health (NICHE), School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland; and.
authors.forename: Gillian R
authors.initials: GR
authors.lastname: Wasson
authors.affiliation: Clinical Medicine, School of Medicine, Trinity College, Dublin, Ireland;
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.affiliation: Northern Ireland Centre for Food & Health (NICHE), School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland; and.
authors.forename: J J
authors.initials: JJ
authors.lastname: Strain
authors.affiliation: Clinical Medicine, School of Medicine, Trinity College, Dublin, Ireland;
authors.forename: Donald G
authors.initials: DG
authors.lastname: Weir
authors.affiliation: Northern Ireland Centre for Food & Health (NICHE), School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland; and.
authors.forename: Mary
authors.initials: M
authors.lastname: Ward
authors.affiliation: Northern Ireland Centre for Food & Health (NICHE), School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland; and.
authors.forename: George
authors.initials: G
authors.lastname: McKerr
authors.affiliation: Departments of Biochemistry and Immunology and.
authors.forename: John M
authors.initials: JM
authors.lastname: Scott
authors.affiliation: Northern Ireland Centre for Food & Health (NICHE), School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland; and cs.downes@ulster.ac.uk.
authors.forename: C Stephen
authors.initials: CS
authors.lastname: Downes
mesh_terms: D018256:Adenomatous Polyps / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D015992:Body Mass Index; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D003113:Colonoscopy; D020552:Comet Assay; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D019175:DNA Methylation / Q000187:drug effects; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D005494:Folic Acid Deficiency / Q000150:complications* / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications; D011127:Polyps; D014498:Uracil / Q000378:metabolism; D014803:Vitamin B Complex / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D014803:Vitamin B Complex; D014498:Uracil; D004247:DNA; D005492:Folic Acid
keywords: DNA methylation; colon cancer; colonocyte; field cancerization; folate; uracil misincorporation