Hostname: page-component-586b7cd67f-r5fsc Total loading time: 0 Render date: 2024-11-29T09:28:48.228Z Has data issue: false hasContentIssue false
  • English
  • Français

Folate, DNA methylation and colo-rectal cancer

Published online by Cambridge University Press:  05 March 2007

Maria Pufulete ,
Peter W. Emery  and
Thomas A. B. Sanders
Maria Pufulete*
Affiliation:
Nutrition Food and Health Research Centre, King's College London, 150 Stamford Street, London, SE1 9NN, UK
Peter W. Emery
Affiliation:
Nutrition Food and Health Research Centre, King's College London, 150 Stamford Street, London, SE1 9NN, UK
Thomas A. B. Sanders
Affiliation:
Nutrition Food and Health Research Centre, King's College London, 150 Stamford Street, London, SE1 9NN, UK
*
*Corresponding author: Maria Pufulete, fax +44 207 848 4185, [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Prospective cohort and case-control studies suggest an association between low folate intake and increased risk of colo-rectal adenoma and cancer. Some, but not all, animal studies indicate that folate supplementation protects against the development of colo-rectal neoplasms, although supraphysiological folate doses have been shown to enhance tumour growth. Folate is a methyl donor for nucleotide synthesis and biological methylation reactions, including DNA methylation. A low dietary folate intake may increase the risk of colo-rectal neoplasia by inducing genomic DNA hypomethylation, which can affect the expression of proto-oncogenes and tumour suppressor genes associated with the development of cancer. Common polymorphisms in genes involved in the methylation pathway, such as methylenetetrahydrofolate reductase and methionine synthase, have been shown to influence risk of colo-rectal neoplasia, with interactions dependent on folate status and/or alcohol intake, which is known to antagonise methyl group availability. There is some evidence to show that DNA from normal-appearing colo-rectal mucosa in individuals with colo-rectal cancer is hypomethylated. In a case-control study DNA methylation in normal-appearing colo-rectal mucosa has been shown to be lower in individuals with colo-rectal cancer (P=0.08) and colo-rectal adenoma (P=0.009) than in controls free of colo-rectal abnormalities. Human intervention trials to date suggest that supraphysiological doses of folate can reverse DNA hypomethylation in colo-rectal mucosa of individuals with colo-rectal neoplasia. In a double-blind randomised placebo-controlled study folate supplementation at physiological doses has been shown to increase DNA methylation in leucocytes (P=0.05) and colonic mucosa (P=0.09). Further studies are required to confirm these findings in larger populations and to define abnormal ranges of DNA methylation.

Keywords

FolateDNA methylationColo-rectal neoplasia
Type
Micronutrient Group Symposium on ‘Micronutrient supplementation: when and why?’
Information
Proceedings of the Nutrition Society , Volume 62 , Issue 2 , May 2003 , pp. 437 - 445
Copyright
Copyright © The Nutrition Society 2003

References

Antequera, F, Boyes, J & Bird, A (1990) High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 62, 503–514CrossRefGoogle ScholarPubMed
Baggott, JE, Vaughn, WH, Juliana, MM, Eto, I, Krumdieck, CL & Grubbs, CJ (1992) Effects of folate deficiency and supplementation on methylnitrosourea-induced rat mammary tumors. Journal of the National Cancer Institute 84, 1740–1744CrossRefGoogle ScholarPubMed
Balaghi, M & Wagner, C (1993) DNA methylation in folate deficiency: use of CpG methylase. Biochemical and Biophysical Research Communications 193, 1184–1190CrossRefGoogle ScholarPubMed
Barak, AJ, Beckenhauer, HC, Kharbanda, KK & Tuma, DJ (2001) Chronic ethanol consumption increases homocysteine accumulation in hepatocytes. Alcohol 25, 77–81CrossRefGoogle ScholarPubMed
Baron, JA, Sandler, RS, Haile, RW, Mandel, JS, Mott, LA & Greenberg, ER (1998) Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas. Journal of the National Cancer Institute 90, 57–62CrossRefGoogle ScholarPubMed
Benito, E, Stiggelbout, A, Bosch, FX, Obrador, A, Kaldor, J, Mulet, M & Munoz, N (1991) Nutritional factors in colorectal cancer risk: a case-control study in Majorca. International Journal of Cancer 49, 161–167CrossRefGoogle Scholar
Bills, ND, Hinrichs, SH, Morgan, R & Clifford, AJ (1992) Delayed tumor onset in transgenic mice fed a low-folate diet. Journal of the National Cancer Institute 84, 332–337CrossRefGoogle ScholarPubMed
Bird, AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321, 209–213CrossRefGoogle ScholarPubMed
Bird, CL, Swendseid, ME, Witte, JS, Shikany, JM, Hunt, IF, Frankl, HD, Lee, ER, Longnecker, MP & Haile, RW (1995) Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps. Cancer Epidemiology Biomarkers and Prevention 4, 709–714Google ScholarPubMed
Boutron-Ruault, MC, Senesse, P, Faivre, J, Couillault, C & Belghiti, C (1996) Folate and alcohol intakes: related or independent roles in the adenoma-carcinoma sequence?. Nutrition and Cancer 26, 337–346CrossRefGoogle ScholarPubMed
Boyes, J & Bird, A (1991) DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell 64, 1123–1134CrossRefGoogle Scholar
Cannon-Albright, LA, Skolnick, MH, Bishop, DT, Lee, RG & Burt, RW (1988) Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. New England Journal of Medicine 319, 533–537CrossRefGoogle ScholarPubMed
Chen, J, Giovannucci, E, Hankinson, SE, Ma, J, Willett, WC, Spiegelman, D, Kelsey, KT & Hunter, DJ (1998) A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma. Carcinogenesis 19, 2129–2132CrossRefGoogle ScholarPubMed
Chen, J, Giovannucci, E, Kelsey, K, Rimm, EB, Stampfer, MJ, Colditz, GA, Spiegelman, D, Willett, WC & Hunter, DJ (1996) A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Research 56, 4862–4864Google ScholarPubMed
folate concentrations in the Framingham study. Journal of Nutrition 131, 3277–3280CrossRefGoogle Scholar
Cravo, M, Fidalgo, P, Pereira, AD, Gouveia-Oliveira, A, Chaves, P, Selhub, J, Mason, JB, Mira, FC & Leitao, CN (1994) DNA methylation as an intermediate biomarker in colorectal cancer: modulation by folic acid supplementation. European Journal of Cancer Prevention 3, 473–479CrossRefGoogle ScholarPubMed
Cravo, ML, Mason, JB, Dayal, Y, Hutchinson, M, Smith, D, Selhub, J & Rosenberg, IH (1992) Folate deficiency enhances the development of colonic neoplasia in dimethylhydrazine-treated rats. Cancer Research 52, 5002–5006Google ScholarPubMed
Cravo, ML, Pinto, AG, Chaves, P, Cruz, JA, Lage, P, Nobre, LC & Costa, MF (1998) Effect of folate supplementation on DNA methylation of rectal mucosa in patients with colonic adenomas: correlation with nutrient intake. Clinical Nutrition 17, 45–49CrossRefGoogle ScholarPubMed
Department, of Health (1998) Nutritional Aspects of the Development of Cancer. Report on Health and Social Subjects no. 48 London H.M. Stationery OfficeGoogle Scholar
Dizik, M, Christman, JK & Wainfan, E (1991) Alterations in expression and methylation of specific genes in livers of rats fed a cancer promoting methyl-deficient diet. Carcinogenesis 12, 1307–1312CrossRefGoogle ScholarPubMed
Duthie, SJ, Narayanan, S, Brand, GM & Grant, G (2000) DNA stability and genomic methylation status in colonocytes isolated from methyl-donor-deficient rats. European Journal of Nutrition 39, 106–111CrossRefGoogle ScholarPubMed
Eichner, ER & Hillman, RS (1971) The evolution of anemia in alcoholic patients. American Journal of Medicine 50, 218–232CrossRefGoogle ScholarPubMed
Fearon, ER & Vogelstein, B (1990) A genetic model for colorectal tumorigenesis. Cell 61, 759–767CrossRefGoogle ScholarPubMed
Feinberg, AP & Vogelstein, B (1983a) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92CrossRefGoogle ScholarPubMed
Feinberg, AP & Vogelstein, B (1983b) Hypomethylation of ras oncogenes in primary human cancers. Biochemical and Biophysical Research Communications 111, 47–54CrossRefGoogle ScholarPubMed
Fenech, M, Aitken, C & Rinaldi, J (1998) Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis 19, 1163–1171CrossRefGoogle ScholarPubMed
Fenoglio, CM & Lane, N (1974) The anatomical precursor of colorectal carcinoma. Cancer 34, 819–823 Suppl.233.0.CO;2-S>CrossRefGoogle ScholarPubMed
Ferraroni, M, La, Vecchia, C, D'Avanzo, B, Negri, E, Franceschi, S, Decarli A (1994) Selected micronutrient intake and the risk of colorectal cancer. British Journal of Cancer 70, 1150–1155CrossRefGoogle ScholarPubMed
Finkelstein, JD, Cello, JP & Kyle, WE (1974) Ethanol-induced changes in methionine metabolism in rat liver. Biochemical and Biophysical Research Communications 61, 525–531CrossRefGoogle ScholarPubMed
Flood, A, Caprario, L, Chaterjee, N, Lacey, JV, Jr, Schairer, C, Schatzkin A (2002) Folate, methionine, alcohol, and colorectal cancer in a prospective study of women in the United States. Cancer Causes and Control 13, 551–561CrossRefGoogle Scholar
Freudenheim, JL, Graham, S, Marshall, JR, Haughey, BP, Cholewinski, S & Wilkinson, G (1991) Folate intake and carcinogenesis of the colon and rectum. International Journal of Epidemiology 20, 368–374CrossRefGoogle ScholarPubMed
Friso, S, Choi, SW, Girelli, D, Mason, JB, Dolnikowski, GG, Bagley, PJ, Olivieri, O, Jacques, PF, Rosenberg, IH, Corrocher, R & Selhub, J (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proceedings of the National Academy of Science USA 99, 5606–5611CrossRefGoogle Scholar
Frosst, P, Blom, HJ, Milos, R, Goyette, P, Sheppard, CA, Matthews, RG, Boers, GJ, den, Heijer, M, Kluijtmans, LA, van den & Heuvel, LP (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics 10, 111–113CrossRefGoogle ScholarPubMed
Fuchs, CS, Willett, WC, Colditz, GA, Hunter, DJ, Stampfer, MJ, Speizer, FE & Giovannucci, EL (2002) The influence of folate and multivitamin use on the familial risk of colon cancer in women. Cancer Epidemiology Biomarkers and Prevention 11, 227–234Google ScholarPubMed
Giovannucci, E, Rimm, EB, Ascherio, A, Stampfer, MJ, Colditz, GA & Willett, WC (1995) Alcohol, low-methionine–low-folate diets, and risk of colon cancer in men. Journal of the National Cancer Institute 87, 265–273CrossRefGoogle ScholarPubMed
Giovannucci, E, Stampfer, MJ, Colditz, GA, Hunter, DJ, Fuchs, C, Rosner, BA, Speizer, FE & Willett, WC (1998) Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Annals of Internal Medicine 129, 517–524CrossRefGoogle ScholarPubMed
Giovannucci, E, Stampfer, MJ, Colditz, GA, Rimm, EB, Trichopoulos, D, Rosner, BA, Speizer, FE & Willett, WC (1993) Folate, methionine, and alcohol intake and risk of colorectal adenoma. Journal of the National Cancer Institute 85, 875–884CrossRefGoogle ScholarPubMed
Glynn, SA, Albanes, D, Pietinen, P, Brown, CC, Rautalahti, M, Tangrea, JA, Gunter, EW, Barrett, MJ, Virtamo, J & Taylor, PR (1996) Colorectal cancer and folate status: a nested case–control study among male smokers. Cancer Epidemiology Biomarkers and Prevention 5, 487–494Google ScholarPubMed
Goelz, SE, Vogelstein, B, Hamilton, SR & Feinberg, AP (1985) Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228, 187–190CrossRefGoogle ScholarPubMed
Greenblatt, MS, Bennett, WP, Hollstein, M & Harris, CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Research 54, 4855–4878Google ScholarPubMed
Harmon, DL, Shields, DC, Woodside, JV, McMaster, D, Yarnell, JW, Young, IS, Peng, K, Shane, B, Evans, AE & Whitehead, AS (1999) Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. Genetics Epidemiology 17, 298–3093.0.CO;2-V>CrossRefGoogle ScholarPubMed
Henning, SM, McKee, RW & Swendseid, ME (1989) Hepatic content of S -adenosylmethionine, S -adenosylhomocysteine and glutathione in rats receiving treatments modulating methyl donor availability. Journal of Nutrition 119, 1478–1482CrossRefGoogle ScholarPubMed
Hiltunen, MO, Alhonen, L, Koistinaho, J, Myohanen, S, Paakkonen, M, Marin, S, Kosma, VM & Janne, J (1997) Hypermethylation of the APC (adenomatous polyposis coli)gene promoter region in human colorectal carcinoma. International Journal of Cancer 70, 644–6483.0.CO;2-V>CrossRefGoogle ScholarPubMed
Hollstein, M, Sidransky, D, Vogelstein, B & Harris, CC (1991) P53 mutations in human cancers. Science 253, 49–53CrossRefGoogle ScholarPubMed
Houlston, RS, Collins, A, Slack, J & Morton, NE (1992) Dominant genes for colorectal cancer are not rare. Annals of Human Genetics 56, 99–103CrossRefGoogle Scholar
Jacob, RA, Gretz, DM, Taylor, PC, James, SJ, Pogribny, IP, Miller, BJ, Henning, SM & Swendseid, ME (1998) Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. Journal of Nutrition 128, 1204–1212CrossRefGoogle ScholarPubMed
Jones, PA, Rideout, WM, III, Shen, JC, Spruck, CH, Tsai YC (1992) Methylation, mutation and cancer. Bioessays 14, 33–36CrossRefGoogle ScholarPubMed
Kamen, B (1997) Folate and antifolate pharmacology. Seminars in Oncology 24 S18Google ScholarPubMed
Kato, I, Dnistrian, AM, Schwartz, M, Toniolo, P, Koenig, K, Shore, RE, Akhmedkhanov, A, Zeleniuch-Jacquotte, A & Riboli, E (1999) Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study. British Journal of Cancer 79, 1917–1922CrossRefGoogle ScholarPubMed
Keshet, I, Lieman-Hurwitz, J & Cedar, H (1986) DNA methylation affects the formation of active chromatin. Cell 44, 535–543CrossRefGoogle ScholarPubMed
Kim, YI, Baik, HW, Fawaz, K, Knox, T, Lee, YM, Norton, R, Libby, E & Mason, JB (2001) Effects of folate supplementation on two provisional molecular markers of colon cancer: a prospective, randomized trial. American Journal of Gastroenterology 96, 184–195CrossRefGoogle ScholarPubMed
Kim, YI, Christman, JK, Fleet, JC, Cravo, ML, Salomon, RN, Smith, D, Ordovas, J, Selhub, J & Mason, JB (1995) Moderate folate deficiency does not cause global hypomethylation of hepatic and colonic DNA or c-myc-specific hypomethylation of colonic DNA in rats. American Journal of Clinical Nutrition 61, 1083–1090CrossRefGoogle ScholarPubMed
Kim, YI, Fawaz, K, Knox, T, Lee, YM, Norton, R, Arora, S, Paiva, L & Mason, JB (1998) Colonic mucosal concentrations of folate correlate well with blood measurements of folate status in persons with colorectal polyps. American Journal of Clinical Nutrition 68, 866–872Google ScholarPubMed
Kim, YI, Miller, JW, da, Costa, KA, Nadeau, M, Smith, D, Selhub, J, Zeisel, SH, Mason JB (1994) Severe folate deficiency causes secondary depletion of choline and phosphocholine in rat liver. Journal of Nutrition 124, 2197–2203CrossRefGoogle ScholarPubMed
Kim, YI, Pogribny, IP, Basnakian, AG, Miller, JW, Selhub, J, James, SJ & Mason, JB (1997) Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. American Journal of Clinical Nutrition 65, 46–52CrossRefGoogle ScholarPubMed
Kim, YI, Pogribny, IP, Salomon, RN, Choi, SW, Smith, DE, James, SJ & Mason, JB (1996a) Exon-specific DNA hypomethylation of the p53 gene of rat colon induced by dimethylhydrazine. Modulation by dietary folate. American Journal of Pathology 149, 1129–1137Google ScholarPubMed
Kim, YI, Salomon, RN, Graeme-Cook, F, Choi, SW, Smith, DE, Dallal, GE & Mason, JB (1996b) Dietary folate protects against the development of macroscopic colonic neoplasia in a dose responsive manner in rats. Gut 39, 732–740CrossRefGoogle Scholar
La, Vecchia, C, Braga, C, Negri, E, Franceschi, S, Russo, A, Conti, E, Falcini, F, Giacosa, A, Montella, M, Decarli A (1997) Intake of selected micronutrients and risk of colorectal cancer. International Journal of Cancer 73, 525–530Google Scholar
Le, Leu, RK, Young, GP, McIntosh GH (2000) Folate deficiency diminishes the occurrence of aberrant crypt foci in the rat colon but does not alter global DNA methylation status. Journal of Gastroenterology and Hepatology 15, 1158–1164CrossRefGoogle Scholar
Levi, F, Pasche, C, Lucchini, F, La, Vecchia C (2000) Selected micronutrients and colorectal cancer. A case-control study from the canton of Vaud, Switzerland. European Journal of Cancer 36, 2115–2119CrossRefGoogle ScholarPubMed
Levine, A, Cantoni, GL & Razin, A (1991) Inhibition of promoter activity by methylation: possible involvement of protein mediators. Proceedings of the National Academy of Science USA 88, 6515–6518CrossRefGoogle ScholarPubMed
Levine, AJ, Siegmund, KD, Ervin, CM, Diep, A, Lee, ER, Frankl, HD & Haile, RW (2000) The methylenetetrahydrofolate reductase 677C→T polymorphism and distal colorectal adenoma risk. Cancer Epidemiology Biomarkers and Prevention 9, 657–663Google ScholarPubMed
Lewis, J & Bird, A (1991) DNA methylation and chromatin structure. FEBS Letters 285, 155–159CrossRefGoogle ScholarPubMed
Li, E, Beard, C & Jaenisch, R (1993) Role for DNA methylation in genomic imprinting. Nature 366, 362–365CrossRefGoogle ScholarPubMed
Locker, J, Reddy, TV & Lombardi, B (1986) DNA methylation and hepatocarcinogenesis in rats fed a choline-devoid diet. Carcinogenesis 7, 1309–1312CrossRefGoogle ScholarPubMed
Ma, J, Stampfer, MJ, Christensen, B, Giovannucci, E, Hunter, DJ, Chen, J, Willett, WC, Selhub, J, Hennekens, CH, Gravel, R & Rozen, R (1999) A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiology Biomarkers and Prevention 8, 825–829Google ScholarPubMed
Ma, J, Stampfer, MJ, Giovannucci, E, Artigas, C, Hunter, DJ, Fuchs, C, Willett, WC, Selhub, J, Hennekens, CH & Rozen, R (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Research 57, 1098–1102Google ScholarPubMed
Mason, JB & Choi, SW (2000) Folate and carcinogenesis: developing a unifying hypothesis. Advances in Enzyme Regulation 40, 127–141CrossRefGoogle ScholarPubMed
Meyer, F & White, E (1993) Alcohol and nutrients in relation to colon cancer in middle-aged adults. American Journal of Epidemiology 138, 225–236CrossRefGoogle ScholarPubMed
Miller, JW, Nadeau, MR, Smith, J, Smith, D & Selhub, J (1994) Folatedeficiency-induced homocysteinaemia in rats: disruption of S -adenosylmethionine's co-ordinate regulation of homocysteine metabolism. Biochemical Journal 298, 415–419CrossRefGoogle Scholar
Muir, C, Waterhouse, J, Mack, T, Powell, J & Whenal, S (1987) Cancer Incidence in Five Continents, Vol. 5 Lyon, France International Agency for Research on CancerGoogle Scholar
Parkin, DM, Pisani, P & Ferlay, J (1999) Global cancer statistics. CA Cancer Journal for Clinicians 49, 33–64CrossRefGoogle ScholarPubMed
Paspatis, GA, Kalafatis, E, Oros, L, Xourgias, V, Koutsioumpa, P & Karamanolis, DG (1995) Folate status and adenomatous colonic polyps. A colonoscopically controlled study. Diseases of the Colon and Rectum 38, 64–67CrossRefGoogle ScholarPubMed
Paspatis, GA & Karamanolis, DG (1994) Folate supplementation and adenomatous colonic polyps. Diseases of the Colon and Rectum 37, 1340–1341CrossRefGoogle ScholarPubMed
Pogribny, IP, Basnakian, AG, Miller, BJ, Lopatina, NG, Poirier, LA & James, SJ (1995) Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Research 55, 1894–1901Google ScholarPubMed
Pogribny, IP, Miller, BJ & James, SJ (1997) Alterations in hepatic p 53 gene methylation patterns during tumor progression with folate/methyl deficiency in the rat. Cancer Letters 115, 31–38CrossRefGoogle Scholar
Pufulete, M, Al-Ghnaniem, R, Khushal, A, Leather, AJM, Rennie, JA, Emery, PW & Sanders, TAB (2002a) Folic acid supplementation increases genomic DNA methylation in patients with colorectal adenoma. Proceedings of the Nutrition Society 61 50AGoogle Scholar
Pufulete, M, Al-Ghnaniem, R, Leather, AJM, Appleby, P, Gout, S, Terry, C, Emery, PW & Sanders, TAB (2003) Folate status, genomic DNA hypomethylation and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 124, 1240–1248CrossRefGoogle ScholarPubMed
Pufulete, M, Emery, PW, Nelson, M & Sanders, TAB (2002b) Validation of a food frequency questionnaire to assess folate intake. British Journal of Nutrition 87, 383–390CrossRefGoogle ScholarPubMed
Rampersaud, GC, Kauwell, GP, Hutson, AD, Cerda, JJ & Bailey, LB (2000) Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. American Journal of Clinical Nutrition 72, 998–1003CrossRefGoogle ScholarPubMed
Rashid, A, Shen, L, Morris, JS, Issa, JP & Hamilton, SR (2001) CpG island methylation in colorectal adenomas. American Journal of Pathology 159, 1129–1135CrossRefGoogle ScholarPubMed
Razin, A & Cedar, H (1991) DNA methylation and gene expression. Microbiology Reviews 55, 451–458CrossRefGoogle ScholarPubMed
Razin, A & Szyf, M (1984) DNA methylation patterns. Formation and function. Biochimica et Biophysica Acta 782, 331–342CrossRefGoogle ScholarPubMed
Reddy, BS, Wang, C-X, Aliaga, C, Rao, CV, Lubet, RA, Steele, VE & Kelloff, GJ (1996) Potential chemopreventive activity of perrilyl alcohol and enhancement of experimental colon carcinogenesis by folic acid and genistein. Proceedings of the American Association of Cancer Research 37 1849AGoogle Scholar
Rideout, WM, III, Coetzee, GA, Olumi, AF, Jones PA (1990) 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249, 1288–1290CrossRefGoogle ScholarPubMed
Romero, JJ, Tamura, T & Halsted, CH (1981) Intestinal absorption of [3H] folic acid in the chronic alcoholic monkey. Gastroenterology 80, 99–102CrossRefGoogle ScholarPubMed
Shannon, B, Gnanasampanthan, S, Beilby, J & Iacopetta, B (2002) A polymorphism in the methylenetetrahydrofolate reductase gene predisposes to colorectal cancers with microsatellite instability. Gut 50, 520–524CrossRefGoogle ScholarPubMed
Shapiro, BD, Goldblum, JR, Hussain, A & Lashner, BA (1997) The role of p53 mutations in colorectal cancer surveillance for ulcerative colitis. Gastroenterology 112 1089AGoogle Scholar
Sharrard, RM, Royds, JA, Rogers, S & Shorthouse, AJ (1992) Patterns of methylation of the c-myc gene in human colorectal cancer progression. British Journal of Cancer 65, 667–672CrossRefGoogle ScholarPubMed
Shaw, S, Jayatilleke, E, Herbert, V & Colman, N (1989) Cleavage of folates during ethanol metabolism. Role of acetaldehyde/xanthine oxidase-generated superoxide. Biochemistry Journal 257, 277–280CrossRefGoogle ScholarPubMed
Shen, JC, Rideout, WM, III, Jones PA (1992) High frequency mutagenesis by a DNA methyltransferase. Cell 71, 1073–1080CrossRefGoogle ScholarPubMed
Shivapurkar, N & Poirier, LA (1983) Tissue levels of S -adenosylmethionine and S -adenosylhomocysteine in rats fed methyldeficient, amino acid-defined diets for one to five weeks. Carcinogenesis 4, 1051–1057CrossRefGoogle ScholarPubMed
Shivapurkar, N, Tang, Z, Frost, A & Alabaster, O (1995) Inhibition of progression of aberrant crypt foci and colon tumor development by vitamin E and beta-carotene in rats on a high-risk diet. Cancer Letters 91, 125–132CrossRefGoogle ScholarPubMed
Slattery, ML, Potter, JD, Samowitz, W, Schaffer, D & Leppert, M (1999) Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiology Biomarkers and Prevention 8, 513–518Google ScholarPubMed
Song, J, Medline, A, Mason, JB, Gallinger, S & Kim, YI (2000a) Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse. Cancer Research 60, 5434–5440Google ScholarPubMed
Song, J, Sohn, KJ, Medline, A, Ash, C, Gallinger, S & Kim, YI (2000b) Chemopreventive effects of dietary folate on intestinal polyps in Apc+/-Msh2-/-mice. Cancer Research 60, 3191–3199Google ScholarPubMed
Stern, LL, Mason, JB, Selhub, J & Choi, SW (2000) Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiology Biomarkers and Prevention 9, 849–853Google ScholarPubMed
Su, LJ & Arab, L (2001) Nutritional status of folate and colon cancer risk: evidence from NHANES I epidemiologic follow-up study. Annals of Epidemiology 11, 65–72CrossRefGoogle ScholarPubMed
Terry, P, Jain, M, Miller, AB, Howe, GR & Rohan, TE (2002) Dietary intake of folic acid and colorectal cancer risk in a cohort of women. International Journal of Cancer 97, 864–867CrossRefGoogle Scholar
Tseng, M, Murray, SC, Kupper, LL & Sandler, RS (1996) Micronutrients and the risk of colorectal adenomas. American Journal of Epidemiology 144, 1005–1014CrossRefGoogle ScholarPubMed
Ulrich, CM, Kampman, E, Bigler, J, Schwartz, SM, Chen, C, Bostick, R, Fosdick, L, Beresford, SA, Yasui, Y & Potter, JD (1999) Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction?. Cancer Epidemiology Biomarkers and Prevention 8, 659–668Google ScholarPubMed
Ulvik, A, Evensen, ET, Lien, EA, Hoff, G, Vollset, SE, Majak, BM & Ueland, PM (2001) Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of colorectum. American Journal of Medical Genetics 101, 246–254CrossRefGoogle ScholarPubMed
Wainfan, E & Poirier, LA (1992) Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. Cancer Research 52 S2071 – S2077Google ScholarPubMed
Wargovich, MJ, Chen, CD, Jimenez, A, Steele, VE, Velasco, M, Stephens, LC, Price, R, Gray, K & Kelloff, GJ (1996) Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat. Cancer Epidemiology Biomarkers and Prevention 5, 355–360Google ScholarPubMed
White, E, Shannon, JS & Patterson, RE (1997) Relationship between vitamin and calcium supplement use and colon cancer. Cancer Epidemiology Biomarkers and Prevention 6, 769–774Google ScholarPubMed
Wilson, MJ, Shivapurkar, N & Poirier, LA (1984) Hypomethylation of hepatic nuclear DNA in rats fed with a carcinogenic methyldeficient diet. Biochemistry Journal 218, 987–990CrossRefGoogle ScholarPubMed
Wolf, SF & Migeon, BR (1985) Clusters of CpG dinucleotides implicated by nuclease hypersensitivity as control elements of housekeeping genes. Nature 314, 467–469CrossRefGoogle ScholarPubMed
Yang, AS, Shen, JC, Zingg, JM, Mi, S & Jones, PA (1995) HhaI and HpaII DNA methyltransferases bind DNA mismatches, methylate uracil and block DNA repair. Nucleic Acids Research 23, 1380–1387CrossRefGoogle ScholarPubMed
Yebra, MJ & Bhagwat, AS (1995) A cytosine methyltransferase converts 5-methylcytosine in DNA to thymine. Biochemistry 34, 14752–14757CrossRefGoogle ScholarPubMed
Yi, J, Wang, ZW, Cang, H, Chen, YY, Zhao, R, Yu, BM & Tang, XM (2001) p16 gene methylation in colorectal cancers associated with Duke's staging. World Journal of Gastroenterology 7, 722–725CrossRefGoogle ScholarPubMed
Zapisek, WF, Cronin, GM, Lyn-Cook, BD & Poirier, LA (1992) The onset of oncogene hypomethylation in the livers of rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis 13, 1869–1872CrossRefGoogle ScholarPubMed