Search tips
Search criteria 


Logo of brjcancerBJC HomepageBJC Advance online publicationBJC Current IssueSubmitting an article to BJCWeb feeds
Br J Cancer. 1999 April; 79(11-12): 1917–1921.
PMCID: PMC2362800

Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study


Accumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case–control study including 105 cases and 523 matched controls from the New York University Women's Health Study cohort. In univariate analyses, the cases had lower serum folate and higher serum homocysteine levels than controls. The difference was more significant for folate (P < 0.001) than for homocysteine (P = 0.04). After ad'justing for potential confounders, the risk of colorectal cancer in the subjects in the highest quartile of serum folate was half that of those in the lowest quartile (odds ratio, OR = 0.52, 95% confidence interval, CI = 0.27–0.97, P-value for trend = 0.04). The OR for the highest quartile of homocysteine, relative to the lowest quartile, was 1.72 (95% CI = 0.83–3.65, P-value for trend = 0.09). In addition, the risk of colorectal cancer was almost twice as high in subjects with below-median serum folate and above-median total alcohol intake compared with those with above-median serum folate and below-median alcohol consumption (OR = 1.99, 95% CI = 0.92–4.29). The potentially protective effects of folate need to be confirmed in clinical trials. © 1999 Cancer Research Campaign

Keywords: colorectal cancer, folate, homocysteine, cohort study women

Full Text

The Full Text of this article is available as a PDF (104K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Baron JA, Sandler RS, Haile RW, Mandel JS, Mott LA, Greenberg ER. Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas. J Natl Cancer Inst. 1998 Jan 7;90(1):57–62. [PubMed]
  • Benito E, Cabeza E, Moreno V, Obrador A, Bosch FX. Diet and colorectal adenomas: a case-control study in Majorca. Int J Cancer. 1993 Sep 9;55(2):213–219. [PubMed]
  • Benito E, Stiggelbout A, Bosch FX, Obrador A, Kaldor J, Mulet M, Muñoz N. Nutritional factors in colorectal cancer risk: a case-control study in Majorca. Int J Cancer. 1991 Sep 9;49(2):161–167. [PubMed]
  • Bird CL, Swendseid ME, Witte JS, Shikany JM, Hunt IF, Frankl HD, Lee ER, Longnecker MP, Haile RW. Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev. 1995 Oct-Nov;4(7):709–714. [PubMed]
  • Block G, Hartman AM, Dresser CM, Carroll MD, Gannon J, Gardner L. A data-based approach to diet questionnaire design and testing. Am J Epidemiol. 1986 Sep;124(3):453–469. [PubMed]
  • Bostick RM, Potter JD, Sellers TA, McKenzie DR, Kushi LH, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. The Iowa Women's Health Study. Am J Epidemiol. 1993 Jun 15;137(12):1302–1317. [PubMed]
  • Broeders MJ, Lambe M, Baron JA, Leon DA. History of childbearing and colorectal cancer risk in women aged less than 60: an analysis of Swedish routine registry data 1960-1984. Int J Cancer. 1996 Apr 10;66(2):170–175. [PubMed]
  • Byers T, Perry G. Dietary carotenes, vitamin C, and vitamin E as protective antioxidants in human cancers. Annu Rev Nutr. 1992;12:139–159. [PubMed]
  • Chen J, Giovannucci E, Kelsey K, Rimm EB, Stampfer MJ, Colditz GA, Spiegelman D, Willett WC, Hunter DJ. A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res. 1996 Nov 1;56(21):4862–4864. [PubMed]
  • Cooper AJ. Biochemistry of sulfur-containing amino acids. Annu Rev Biochem. 1983;52:187–222. [PubMed]
  • Cravo ML, Mason JB, Dayal Y, Hutchinson M, Smith D, Selhub J, Rosenberg IH. Folate deficiency enhances the development of colonic neoplasia in dimethylhydrazine-treated rats. Cancer Res. 1992 Sep 15;52(18):5002–5006. [PubMed]
  • Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981 Jun;66(6):1191–1308. [PubMed]
  • Eichner ER, Hillman RS. The evolution of anemia in alcoholic patients. Am J Med. 1971 Feb;50(2):218–232. [PubMed]
  • Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res. 1988 Mar 1;48(5):1159–1161. [PubMed]
  • Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983 Jan 6;301(5895):89–92. [PubMed]
  • Ferraroni M, La Vecchia C, D'Avanzo B, Negri E, Franceschi S, Decarli A. Selected micronutrient intake and the risk of colorectal cancer. Br J Cancer. 1994 Dec;70(6):1150–1155. [PMC free article] [PubMed]
  • Freudenheim JL, Graham S, Marshall JR, Haughey BP, Cholewinski S, Wilkinson G. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol. 1991 Jun;20(2):368–374. [PubMed]
  • Giltay EJ, Hoogeveen EK, Elbers JM, Gooren LJ, Asscheman H, Stehouwer CD. Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females. J Clin Endocrinol Metab. 1998 Feb;83(2):550–553. [PubMed]
  • Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC. Alcohol, low-methionine--low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst. 1995 Feb 15;87(4):265–273. [PubMed]
  • Giovannucci E, Stampfer MJ, Colditz GA, Rimm EB, Trichopoulos D, Rosner BA, Speizer FE, Willett WC. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst. 1993 Jun 2;85(11):875–884. [PubMed]
  • Glynn SA, Albanes D, Pietinen P, Brown CC, Rautalahti M, Tangrea JA, Gunter EW, Barrett MJ, Virtamo J, Taylor PR. Colorectal cancer and folate status: a nested case-control study among male smokers. Cancer Epidemiol Biomarkers Prev. 1996 Jul;5(7):487–494. [PubMed]
  • Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985 Apr 12;228(4696):187–190. [PubMed]
  • Halline AG, Dudeja PK, Brasitus TA. 1,2-Dimethylhydrazine-induced premalignant alterations in the S-adenosylmethionine/S-adenosylhomocysteine ratio and membrane lipid lateral diffusion of the rat distal colon. Biochim Biophys Acta. 1988 Sep 15;944(1):101–107. [PubMed]
  • Hoffman RM. Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis. A review and synthesis. Biochim Biophys Acta. 1984;738(1-2):49–87. [PubMed]
  • Hook EB, Regal RR. Capture-recapture methods in epidemiology: methods and limitations. Epidemiol Rev. 1995;17(2):243–264. [PubMed]
  • Howell MA. Deit as an etiological factor in the development of cancers of the colon and rectum. J Chronic Dis. 1975 Feb;28(2):67–80. [PubMed]
  • Jacob RA, Wu MM, Henning SM, Swendseid ME. Homocysteine increases as folate decreases in plasma of healthy men during short-term dietary folate and methyl group restriction. J Nutr. 1994 Jul;124(7):1072–1080. [PubMed]
  • Kang SS, Wong PW, Norusis M. Homocysteinemia due to folate deficiency. Metabolism. 1987 May;36(5):458–462. [PubMed]
  • Kato I, Akhmedkhanov A, Koenig K, Toniolo PG, Shore RE, Riboli E. Prospective study of diet and female colorectal cancer: the New York University Women's Health Study. Nutr Cancer. 1997;28(3):276–281. [PubMed]
  • Kim YI, Pogribny IP, Basnakian AG, Miller JW, Selhub J, James SJ, Mason JB. Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am J Clin Nutr. 1997 Jan;65(1):46–52. [PubMed]
  • Kim YI, Salomon RN, Graeme-Cook F, Choi SW, Smith DE, Dallal GE, Mason JB. Dietary folate protects against the development of macroscopic colonic neoplasia in a dose responsive manner in rats. Gut. 1996 Nov;39(5):732–740. [PMC free article] [PubMed]
  • Lashner BA. Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol. 1993;119(9):549–554. [PubMed]
  • Letellier M, Lévesque A, Daigle F, Grant A. Performance evaluation of automated immunoassays on the Technicon Immuno 1 system. Clin Chem. 1996 Oct;42(10):1695–1701. [PubMed]
  • Lyon JL, Mahoney AW, West DW, Gardner JW, Smith KR, Sorenson AW, Stanish W. Energy intake: its relationship to colon cancer risk. J Natl Cancer Inst. 1987 May;78(5):853–861. [PubMed]
  • Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, Willett WC, Selhub J, Hennekens CH, Rozen R. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 1997 Mar 15;57(6):1098–1102. [PubMed]
  • Nyce J, Weinhouse S, Magee PN. 5-Methylcytosine depletion during tumour development: an extension of the miscoding concept. Br J Cancer. 1983 Oct;48(4):463–475. [PMC free article] [PubMed]
  • O'Keefe CA, Bailey LB, Thomas EA, Hofler SA, Davis BA, Cerda JJ, Gregory JF., 3rd Controlled dietary folate affects folate status in nonpregnant women. J Nutr. 1995 Oct;125(10):2717–2725. [PubMed]
  • Paspatis GA, Kalafatis E, Oros L, Xourgias V, Koutsioumpa P, Karamanolis DG. Folate status and adenomatous colonic polyps. A colonoscopically controlled study. Dis Colon Rectum. 1995 Jan;38(1):64–68. [PubMed]
  • Romero JJ, Tamura T, Halsted CH. Intestinal absorption of [3H]folic acid in the chronic alcoholic monkey. Gastroenterology. 1981 Jan;80(1):99–102. [PubMed]
  • Rose DP, Boyar AP, Wynder EL. International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer. 1986 Dec 1;58(11):2363–2371. [PubMed]
  • Shaw S, Jayatilleke E, Herbert V, Colman N. Cleavage of folates during ethanol metabolism. Role of acetaldehyde/xanthine oxidase-generated superoxide. Biochem J. 1989 Jan 1;257(1):277–280. [PubMed]
  • Sinha R, Rothman N, Brown ED, Mark SD, Hoover RN, Caporaso NE, Levander OA, Knize MG, Lang NP, Kadlubar FF. Pan-fried meat containing high levels of heterocyclic aromatic amines but low levels of polycyclic aromatic hydrocarbons induces cytochrome P4501A2 activity in humans. Cancer Res. 1994 Dec 1;54(23):6154–6159. [PubMed]
  • Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest. 1988 Feb;81(2):466–474. [PMC free article] [PubMed]
  • Thune I, Lund E. Physical activity and risk of colorectal cancer in men and women. Br J Cancer. 1996 May;73(9):1134–1140. [PMC free article] [PubMed]
  • Toniolo PG, Levitz M, Zeleniuch-Jacquotte A, Banerjee S, Koenig KL, Shore RE, Strax P, Pasternack BS. A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst. 1995 Feb 1;87(3):190–197. [PubMed]
  • Toniolo PG, Pasternack BS, Shore RE, Sonnenschein E, Koenig KL, Rosenberg C, Strax P, Strax S. Endogenous hormones and breast cancer: a prospective cohort study. Breast Cancer Res Treat. 1991 May;18 (Suppl 1):S23–S26. [PubMed]
  • Toniolo P, Riboli E, Shore RE, Pasternack BS. Consumption of meat, animal products, protein, and fat and risk of breast cancer: a prospective cohort study in New York. Epidemiology. 1994 Jul;5(4):391–397. [PubMed]
  • Trock B, Lanza E, Greenwald P. Dietary fiber, vegetables, and colon cancer: critical review and meta-analyses of the epidemiologic evidence. J Natl Cancer Inst. 1990 Apr 18;82(8):650–661. [PubMed]
  • Tseng M, Murray SC, Kupper LL, Sandler RS. Micronutrients and the risk of colorectal adenomas. Am J Epidemiol. 1996 Dec 1;144(11):1005–1014. [PubMed]
  • Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ. Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr. 1993 Jan;57(1):47–53. [PubMed]
  • Vester B, Rasmussen K. High performance liquid chromatography method for rapid and accurate determination of homocysteine in plasma and serum. Eur J Clin Chem Clin Biochem. 1991 Sep;29(9):549–554. [PubMed]
  • Wainfan E, Poirier LA. Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. Cancer Res. 1992 Apr 1;52(7 Suppl):2071s–2077s. [PubMed]
  • Willett W. The search for the causes of breast and colon cancer. Nature. 1989 Mar 30;338(6214):389–394. [PubMed]
  • Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Speizer FE. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med. 1990 Dec 13;323(24):1664–1672. [PubMed]
  • Wurzelmann JI, Silver A, Schreinemachers DM, Sandler RS, Everson RB. Iron intake and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 1996 Jul;5(7):503–507. [PubMed]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK