Abstract
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 (104.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Baron J. A., Sandler R. S., Haile R. W., Mandel J. S., Mott L. A., Greenberg E. R. Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas. J Natl Cancer Inst. 1998 Jan 7;90(1):57–62. doi: 10.1093/jnci/90.1.57. [DOI] [PubMed] [Google Scholar]
- Benito E., Cabeza E., Moreno V., Obrador A., Bosch F. X. Diet and colorectal adenomas: a case-control study in Majorca. Int J Cancer. 1993 Sep 9;55(2):213–219. doi: 10.1002/ijc.2910550208. [DOI] [PubMed] [Google Scholar]
- Benito E., Stiggelbout A., Bosch F. X., 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. doi: 10.1002/ijc.2910490202. [DOI] [PubMed] [Google Scholar]
- Bird C. L., Swendseid M. E., Witte J. S., Shikany J. M., Hunt I. F., Frankl H. D., Lee E. R., Longnecker M. P., Haile R. W. 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] [Google Scholar]
- Block G., Hartman A. M., Dresser C. M., Carroll M. D., Gannon J., Gardner L. A data-based approach to diet questionnaire design and testing. Am J Epidemiol. 1986 Sep;124(3):453–469. doi: 10.1093/oxfordjournals.aje.a114416. [DOI] [PubMed] [Google Scholar]
- Bostick R. M., Potter J. D., Sellers T. A., McKenzie D. R., Kushi L. H., Folsom A. R. 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. doi: 10.1093/oxfordjournals.aje.a116640. [DOI] [PubMed] [Google Scholar]
- Broeders M. J., Lambe M., Baron J. A., Leon D. A. 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. doi: 10.1002/(SICI)1097-0215(19960410)66:2<170::AID-IJC5>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
- Byers T., Perry G. Dietary carotenes, vitamin C, and vitamin E as protective antioxidants in human cancers. Annu Rev Nutr. 1992;12:139–159. doi: 10.1146/annurev.nu.12.070192.001035. [DOI] [PubMed] [Google Scholar]
- Chen J., Giovannucci E., Kelsey K., Rimm E. B., Stampfer M. J., Colditz G. A., Spiegelman D., Willett W. C., Hunter D. J. A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res. 1996 Nov 1;56(21):4862–4864. [PubMed] [Google Scholar]
- Cooper A. J. Biochemistry of sulfur-containing amino acids. Annu Rev Biochem. 1983;52:187–222. doi: 10.1146/annurev.bi.52.070183.001155. [DOI] [PubMed] [Google Scholar]
- Cravo M. L., Mason J. B., Dayal Y., Hutchinson M., Smith D., Selhub J., Rosenberg I. H. Folate deficiency enhances the development of colonic neoplasia in dimethylhydrazine-treated rats. Cancer Res. 1992 Sep 15;52(18):5002–5006. [PubMed] [Google Scholar]
- 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] [Google Scholar]
- Eichner E. R., Hillman R. S. The evolution of anemia in alcoholic patients. Am J Med. 1971 Feb;50(2):218–232. doi: 10.1016/0002-9343(71)90151-3. [DOI] [PubMed] [Google Scholar]
- Feinberg A. P., Gehrke C. W., Kuo K. C., Ehrlich M. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res. 1988 Mar 1;48(5):1159–1161. [PubMed] [Google Scholar]
- Feinberg A. P., Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983 Jan 6;301(5895):89–92. doi: 10.1038/301089a0. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1038/bjc.1994.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Freudenheim J. L., Graham S., Marshall J. R., Haughey B. P., Cholewinski S., Wilkinson G. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol. 1991 Jun;20(2):368–374. doi: 10.1093/ije/20.2.368. [DOI] [PubMed] [Google Scholar]
- Giltay E. J., Hoogeveen E. K., Elbers J. M., Gooren L. J., Asscheman H., Stehouwer C. D. 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. doi: 10.1210/jcem.83.2.4574. [DOI] [PubMed] [Google Scholar]
- Giovannucci E., Rimm E. B., Ascherio A., Stampfer M. J., Colditz G. A., Willett W. C. Alcohol, low-methionine--low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst. 1995 Feb 15;87(4):265–273. doi: 10.1093/jnci/87.4.265. [DOI] [PubMed] [Google Scholar]
- Giovannucci E., Stampfer M. J., Colditz G. A., Rimm E. B., Trichopoulos D., Rosner B. A., Speizer F. E., Willett W. C. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst. 1993 Jun 2;85(11):875–884. doi: 10.1093/jnci/85.11.875. [DOI] [PubMed] [Google Scholar]
- Glynn S. A., Albanes D., Pietinen P., Brown C. C., Rautalahti M., Tangrea J. A., Gunter E. W., Barrett M. J., Virtamo J., Taylor P. R. Colorectal cancer and folate status: a nested case-control study among male smokers. Cancer Epidemiol Biomarkers Prev. 1996 Jul;5(7):487–494. [PubMed] [Google Scholar]
- Goelz S. E., Vogelstein B., Hamilton S. R., Feinberg A. P. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985 Apr 12;228(4696):187–190. doi: 10.1126/science.2579435. [DOI] [PubMed] [Google Scholar]
- Halline A. G., Dudeja P. K., Brasitus T. A. 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. doi: 10.1016/0005-2736(88)90322-7. [DOI] [PubMed] [Google Scholar]
- Hoffman R. M. Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis. A review and synthesis. Biochim Biophys Acta. 1984;738(1-2):49–87. doi: 10.1016/0304-419x(84)90019-2. [DOI] [PubMed] [Google Scholar]
- Hook E. B., Regal R. R. Capture-recapture methods in epidemiology: methods and limitations. Epidemiol Rev. 1995;17(2):243–264. doi: 10.1093/oxfordjournals.epirev.a036192. [DOI] [PubMed] [Google Scholar]
- Howell M. A. Deit as an etiological factor in the development of cancers of the colon and rectum. J Chronic Dis. 1975 Feb;28(2):67–80. doi: 10.1016/0021-9681(75)90063-6. [DOI] [PubMed] [Google Scholar]
- Jacob R. A., Wu M. M., Henning S. M., Swendseid M. E. 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. doi: 10.1093/jn/124.7.1072. [DOI] [PubMed] [Google Scholar]
- Kang S. S., Wong P. W., Norusis M. Homocysteinemia due to folate deficiency. Metabolism. 1987 May;36(5):458–462. doi: 10.1016/0026-0495(87)90043-6. [DOI] [PubMed] [Google Scholar]
- Kato I., Akhmedkhanov A., Koenig K., Toniolo P. G., Shore R. E., 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. doi: 10.1080/01635589709514588. [DOI] [PubMed] [Google Scholar]
- Kim Y. I., Pogribny I. P., Basnakian A. G., Miller J. W., Selhub J., James S. J., Mason J. B. 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. doi: 10.1093/ajcn/65.1.46. [DOI] [PubMed] [Google Scholar]
- Kim Y. I., Salomon R. N., Graeme-Cook F., Choi S. W., Smith D. E., Dallal G. E., Mason J. B. Dietary folate protects against the development of macroscopic colonic neoplasia in a dose responsive manner in rats. Gut. 1996 Nov;39(5):732–740. doi: 10.1136/gut.39.5.732. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lashner B. A. 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. doi: 10.1007/BF01686465. [DOI] [PubMed] [Google Scholar]
- 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] [Google Scholar]
- Lyon J. L., Mahoney A. W., West D. W., Gardner J. W., Smith K. R., Sorenson A. W., Stanish W. Energy intake: its relationship to colon cancer risk. J Natl Cancer Inst. 1987 May;78(5):853–861. [PubMed] [Google Scholar]
- Ma J., Stampfer M. J., Giovannucci E., Artigas C., Hunter D. J., Fuchs C., Willett W. C., Selhub J., Hennekens C. H., Rozen R. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 1997 Mar 15;57(6):1098–1102. [PubMed] [Google Scholar]
- Nyce J., Weinhouse S., Magee P. N. 5-Methylcytosine depletion during tumour development: an extension of the miscoding concept. Br J Cancer. 1983 Oct;48(4):463–475. doi: 10.1038/bjc.1983.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
- O'Keefe C. A., Bailey L. B., Thomas E. A., Hofler S. A., Davis B. A., Cerda J. J., Gregory J. F., 3rd Controlled dietary folate affects folate status in nonpregnant women. J Nutr. 1995 Oct;125(10):2717–2725. doi: 10.1093/jn/125.10.2717. [DOI] [PubMed] [Google Scholar]
- Paspatis G. A., Kalafatis E., Oros L., Xourgias V., Koutsioumpa P., Karamanolis D. G. Folate status and adenomatous colonic polyps. A colonoscopically controlled study. Dis Colon Rectum. 1995 Jan;38(1):64–68. doi: 10.1007/BF02053860. [DOI] [PubMed] [Google Scholar]
- Romero J. J., Tamura T., Halsted C. H. Intestinal absorption of [3H]folic acid in the chronic alcoholic monkey. Gastroenterology. 1981 Jan;80(1):99–102. [PubMed] [Google Scholar]
- Rose D. P., Boyar A. P., Wynder E. L. 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. doi: 10.1002/1097-0142(19861201)58:11<2363::aid-cncr2820581102>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1042/bj2570277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sinha R., Rothman N., Brown E. D., Mark S. D., Hoover R. N., Caporaso N. E., Levander O. A., Knize M. G., Lang N. P., Kadlubar F. F. 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] [Google Scholar]
- Stabler S. P., Marcell P. D., Podell E. R., Allen R. H., Savage D. G., 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. doi: 10.1172/JCI113343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thune I., Lund E. Physical activity and risk of colorectal cancer in men and women. Br J Cancer. 1996 May;73(9):1134–1140. doi: 10.1038/bjc.1996.218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Toniolo P. G., Levitz M., Zeleniuch-Jacquotte A., Banerjee S., Koenig K. L., Shore R. E., Strax P., Pasternack B. S. A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst. 1995 Feb 1;87(3):190–197. doi: 10.1093/jnci/87.3.190. [DOI] [PubMed] [Google Scholar]
- Toniolo P. G., Pasternack B. S., Shore R. E., Sonnenschein E., Koenig K. L., 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. doi: 10.1007/BF02633522. [DOI] [PubMed] [Google Scholar]
- Toniolo P., Riboli E., Shore R. E., Pasternack B. S. 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. doi: 10.1097/00001648-199407000-00003. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1093/jnci/82.8.650. [DOI] [PubMed] [Google Scholar]
- Tseng M., Murray S. C., Kupper L. L., Sandler R. S. Micronutrients and the risk of colorectal adenomas. Am J Epidemiol. 1996 Dec 1;144(11):1005–1014. doi: 10.1093/oxfordjournals.aje.a008871. [DOI] [PubMed] [Google Scholar]
- Ubbink J. B., Vermaak W. J., van der Merwe A., Becker P. J. Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr. 1993 Jan;57(1):47–53. doi: 10.1093/ajcn/57.1.47. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1515/cclm.1991.29.9.549. [DOI] [PubMed] [Google Scholar]
- Wainfan E., Poirier L. A. Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. Cancer Res. 1992 Apr 1;52(7 Suppl):2071s–2077s. [PubMed] [Google Scholar]
- Willett W. C., Stampfer M. J., Colditz G. A., Rosner B. A., Speizer F. E. 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. doi: 10.1056/NEJM199012133232404. [DOI] [PubMed] [Google Scholar]
- Willett W. The search for the causes of breast and colon cancer. Nature. 1989 Mar 30;338(6214):389–394. doi: 10.1038/338389a0. [DOI] [PubMed] [Google Scholar]
- Wurzelmann J. I., Silver A., Schreinemachers D. M., Sandler R. S., Everson R. B. Iron intake and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 1996 Jul;5(7):503–507. [PubMed] [Google Scholar]