title: Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa.
abstract: Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1), using bisulfite pyrosequencing. We used generalized estimating equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percentage methylation was significantly higher in the rectum than in the right colon (P = 0.001). For each 10 years of age, we observed a 1.7% increase in methylation level for ERα and a 2.9% increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia.
authors.affiliation: Department of Medicine, Dartmouth Medical School, Evergreen Center, Lebanon, NH 03756, USA. john.a.baron@dartmouth.edu
authors.forename: Kristin
authors.initials: K
authors.lastname: Wallace
authors.forename: Maria V
authors.initials: MV
authors.lastname: Grau
authors.forename: A Joan
authors.initials: AJ
authors.lastname: Levine
authors.forename: Lanlan
authors.initials: L
authors.lastname: Shen
authors.forename: Randala
authors.initials: R
authors.lastname: Hamdan
authors.forename: Xinli
authors.initials: X
authors.lastname: Chen
authors.forename: Jiang
authors.initials: J
authors.lastname: Gui
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Barry
authors.forename: Dennis
authors.initials: D
authors.lastname: Ahnen
authors.forename: Gail
authors.initials: G
authors.lastname: McKeown-Eyssen
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Jean Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000236:Adenoma / Q000097:blood / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000097:blood; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003111:Colonic Polyps / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D004311:Double-Blind Method; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005500:Follow-Up Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010919:Placebos; D011379:Prognosis; D012007:Rectum / Q000378:metabolism* / Q000473:pathology; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D005492:Folic Acid; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010919:Placebos; C506487:ESR1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins