Folate

  • Cornelia M. Ulrich
  • Xinran Xu
  • Amy Liu
  • Jia Chen
Chapter
Part of the Nutrition and Health book series (NH)

Key Points

1. Folate is a generic descriptor for a water-soluble B-complex vitamin that functions in one-carbon transfer reactions and exists in multiple chemical forms. Most naturally occurring folates are poly-glutamated forms, which enable their retention in the cell. However, folic acid is the most oxidized and stable form of folate, rarely found in food, yet used commonly in vitamin supplements and fortified foods.

2. The nutrient folate is a B vitamin that provides methyl groups for one-carbon transfer reactions, including those supporting the synthesis of nucleotides and methylation reactions. A higher folate status has been consistently associated with decreased cancers risks of the colorectum, esophagus, and possibly pancreas. A decreased breast cancer risk with higher folate intakes among alcohol consumers has also been suggested.

3. Folate is also important for the synthesis of S-adenosylmethionine (SAM), the universal donor of methyl groups necessary for DNA methylation. Together with changes in the histone code, DNA methylation is an important epigenetic mode of gene silencing.

4. Recently, two trials involving the prevention of recurring colorectal polyps have proven that folic acid and aspirin administration did not prevent the recurrence of colorectal adenomas. Conversely, animal studies have proven an inverse relationship between folate deficiency and increased colorectal cancer. The unexpected results of the human prevention trials were interpreted in light of the accumulating evidence from the animal studies.

5. Results from a simulation investigating a dual role of folate in carcinogens conducted by Luebeck et al. indicate that the effects of folate on colon carcinogenesis are age- and dose-dependent, with predominantly increased risk if the amount of folate given were to increase cellular replication rates by 20%. However, a lack of quantitative estimates of the response of tissues or cancer precursors to folate or folic acid supplementation limits this modeling.

Key Words

Folate methylation diets DNA methylation cancer risk 
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References

  1. 1.
    Wagner, C. (1995) Biochemical Role of Folate in Cellular metabolism. Folate in Health and Disease. New York: Marcel Dekker.Google Scholar
  2. 2.
    Institute of Medicine (1998) Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press.Google Scholar
  3. 3.
    Ulrich, C.M., Robien, K., and McLeod, H.L. (2003) Cancer pharmacogenetics: Polymorphisms, pathways and beyond. Nat Rev Cancer 3, 912–20.Google Scholar
  4. 4.
    Stover, P.J. (2004) Physiology of folate and vitamin B12 in health and disease. Nutr Rev 62, S3–S12, discussion S13.PubMedCrossRefGoogle Scholar
  5. 5.
    Woeller, C.F., Anderson, D.D., Szebenyi, D.M., and Stover, P.J. (2007) Evidence for small ubiquitin-like modifier-dependent nuclear import of the thymidylate biosynthesis pathway. J Biol Chem 282, 17623–31.PubMedCrossRefGoogle Scholar
  6. 6.
    Choi, S.W., and Mason, J.B. (2002) Folate status: Effects on pathways of colorectal carcinogenesis. J Nutr 132, 2413S–2418S.PubMedGoogle Scholar
  7. 7.
    Chu, E., and Allegra, C. (1996) Antifolates. In: Chabner, B., and Longo, D., eds. Cancer Chemotherapy and Biotherapy. 109–48, Philadelphia: Lippincott-Raven Publishers.Google Scholar
  8. 8.
    Danenberg, P.V., Malli, H., and Swenson, S. (1999) Thymidylate synthase inhibitors. Semin Oncol 26, 621–31.PubMedGoogle Scholar
  9. 9.
    Laird, P.W. (2005) Cancer epigenetics. Hum Mol Genet 14(Spec No 1), R65–R76.PubMedCrossRefGoogle Scholar
  10. 10.
    Jones, P.A., and Baylin, S.B. (2002) The fundamental role of epigenetic events in cancer. Nat Rev Gene 3, 415–28.CrossRefGoogle Scholar
  11. 11.
    Toyota, M., and Issa, J.P. (2005) Epigenetic changes in solid and hematopoietic tumors. Semin Oncol 32, 521–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Ulrich, C.M., Curtin, K., Samowitz, W., Bigler, J., Potter, J.D., Caan, B., and Slattery, M.L. (2005) MTHFR variants reduce the risk of G:C->A:T transition mutations within the p53 tumor suppressor gene in colon tumors. J Nutr 135, 2462–67.PubMedGoogle Scholar
  13. 13.
    Jones, P.A., and Gonzalgo, M.L. (1997) Altered DNA methylation and genome instability: A new pathway to cancer? Proc Natl Acad Sci USA 94, 2103–05.PubMedCrossRefGoogle Scholar
  14. 14.
    Rampersaud, G.C., Kauwell, G.P., Hutson, A.D., Cerda, J.J., and Bailey, L.B. (2000) Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. Am J Clin Nutr 72, 998–1003.PubMedGoogle Scholar
  15. 15.
    Kim, Y.I. (2004) Folate and DNA methylation: A mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Prev 13, 511–19.PubMedGoogle Scholar
  16. 16.
    Davis, S., Stacpoole, P.W., Bailey, L.B., and Gregory, J.F., 3rd. (2002) C677T MTHFR genotype & homocysteine remethylation; effects of folate depletion. Exp Biol.Google Scholar
  17. 17.
    Shelnutt, K.P., Kauwell, G.P., Gregory, J.F., 3rd., Maneval, D.R., Quinlivan, E.P., Theriaque, D.W., Henderson, G.N., and Bailey, L.B. (2004) Methylenetetrahydrofolate reductase 677C–>T polymorphism affects DNA methylation in response to controlled folate intake in young women. J Nutr Biochem 15, 554–60.PubMedCrossRefGoogle Scholar
  18. 18.
    Pufulete, M., Al-Ghnaniem, R., Khushal, A., Appleby, P., Harris, N., Gout, S., Emery, P.W., and Sanders, T.A. (2005) Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma. Gut 54, 648–53.PubMedCrossRefGoogle Scholar
  19. 19.
    van den Donk, M., van Engeland, M., Pellis, L., Witteman, B.J., Kok, F.J., Keijer, J., and Kampman, E. (2007) Dietary folate intake in combination with MTHFR C677T genotype and promoter methylation of tumor suppressor and DNA repair genes in sporadic colorectal adenomas. Cancer Epidemiol Biomarkers Prev 16, 327–33.PubMedCrossRefGoogle Scholar
  20. 20.
    Waterland, R.A., and Jirtle, R.L. (2003) Transposable elements: Targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23, 5293–300.PubMedCrossRefGoogle Scholar
  21. 21.
    Dolinoy, D.C., Huang, D., and Jirtle, R.L. (2007) Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci USA 104, 13056–61.PubMedCrossRefGoogle Scholar
  22. 22.
    Paz, M.F., Avila, S., Fraga, M.F., Pollan, M., Capella, G., Peinado, M.A., Sanchez-Cespedes, M., Herman, J.G., and Esteller, M. (2002) Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors. Cancer Res 62, 4519–24.PubMedGoogle Scholar
  23. 23.
    Oyama, K., Kawakami, K., Maeda, K., Ishiguro, K., and Watanabe, G. (2004) The association between methylenetetrahydrofolate reductase polymorphism and promoter methylation in proximal colon cancer. Anticancer Res 24, 649–54.PubMedGoogle Scholar
  24. 24.
    van Engeland, M., Weijenberg, M.P., Roemen, G.M., Brink, M., de Bruine, A.P., Goldbohm, R.A., van den Brandt, P.A., Baylin, S.B., de Goeij, A.F., and Herman, J.G. (2003) Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: The Netherlands cohort study on diet and cancer. Cancer Res 63, 3133–37.PubMedGoogle Scholar
  25. 25.
    Curtin, K., Slattery, M.L., Ulrich, C.M., Bigler, J., Levin, T.R., Wolff, R.K., Albertsen, H., Potter, J.D., and Samowitz, W.S. (2007) Genetic polymorphisms in one-carbon metabolism: Associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet. Carcinogenesis 28, 1672–79.PubMedCrossRefGoogle Scholar
  26. 26.
    Slattery, M.L., Curtin, K., Sweeney, C., Levin, T.R., Potter, J., Wolff, R.K., Albertsen, H., and Samowitz, W.S. (2007) Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer. Int J Cancer 120, 656–63.PubMedCrossRefGoogle Scholar
  27. 27.
    Kawakami, K., Ooyama, A., Ruszkiewicz, A., Jin, M., Watanabe, G., Moore, J., Oka, T., Iacopetta, B., and Minamoto, T. (2008) Low expression of gamma-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype. Br J Cancer 98, 1555–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Martinez, M.E., Giovannucci, E., Jiang, R., Henning, S.M., Jacobs, E.T., Thompson, P., Smith-Warner, S.A., and Alberts, D.S. (2006) Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence. Int J Cancer 119, 1440–46.PubMedCrossRefGoogle Scholar
  29. 29.
    Honein, M.A., Paulozzi, L.J., Mathews, T.J., Erickson, J.D., and Wong, L.Y. (2001) Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 285, 2981–86.PubMedCrossRefGoogle Scholar
  30. 30.
    Quinlivan, E.P., and Gregory, J.F., 3rd. (2003) Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr 77, 221–25.PubMedGoogle Scholar
  31. 31.
    Jacques, P.F., Selhub, J., Bostom, A.G., Wilson, P.W., and Rosenberg, I.H. (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 340, 1449–54.PubMedCrossRefGoogle Scholar
  32. 32.
    Brownie, S., and Myers, S. (2004) Wading through the quagmire: Making sense of dietary supplement utilization. Nutr Rev 62, 276–82.PubMedCrossRefGoogle Scholar
  33. 33.
    Harrison, R.A., Holt, D., Pattison, D.J., and Elton, P.J. (2004) Are those in need taking dietary supplements? A survey of 21 923 adults. Br J Nutr 91, 617–23.PubMedCrossRefGoogle Scholar
  34. 34.
    Huang, H.-Y., Caballero, B., Chang, S., Alberg, A.J., Semba, R.D., Schneyer, C.R., Wilson, R.F., Cheng, T.-Y., Vassy, J., Prokopowicz, G., Barnes, G.J., 2nd., and Bass, E.B. (2006) The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: A systematic review for a National Institutes of Health state-of-the-science conference. Ann Intern Med 145, 372–85.PubMedGoogle Scholar
  35. 35.
    Sanjoaquin, M.A., Allen, N., Couto, E., Roddam, A.W., and Key, T.J. (2005) Folate intake and colorectal cancer risk: A meta-analytical approach. Int J Cancer 113, 825–28.PubMedCrossRefGoogle Scholar
  36. 36.
    Larsson, S.C., Giovannucci, E., and Wolk, A. (2007) Folate and risk of breast cancer: A meta-analysis. J Natl Cancer Inst 99, 64–76.PubMedCrossRefGoogle Scholar
  37. 37.
    Lewis, S.J., Harbord, R.M., Harris, R., and Smith, G.D. (2006) Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk. J Natl Cancer Inst 98, 1607–22.PubMedCrossRefGoogle Scholar
  38. 38.
    Larsson, S.C., Giovannucci, E., and Wolk, A. (2006) Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: A meta-analysis. Gastroenterology 131, 1271–83.PubMedCrossRefGoogle Scholar
  39. 39.
    Cho, E., Hunter, D.J., Spiegelman, D., Albanes, D., Beeson, W.L., van den Brandt, P.A., Colditz, G.A., Feskanich, D., Folsom, A.R., Fraser, G.E., Freudenheim, J.L., Giovannucci, E., Goldbohm, R.A., Graham, S., Miller, A.B., Rohan, T.E., Sellers, T.A., Virtamo, J., Willett, W.C., and Smith-Warner, S.A. (2006) Intakes of vitamins A, C and E and folate and multivitamins and lung cancer: A pooled analysis of 8 prospective studies. Int J Cancer 118, 970–78.PubMedCrossRefGoogle Scholar
  40. 40.
    Larsson, S.C., Giovannucci, E., and Wolk, A. (2005) A prospective study of dietary folate intake and risk of colorectal cancer: Modification by caffeine intake and cigarette smoking. Cancer Epidemiol Biomarkers Prev 14, 740–43.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhang, S.M., Moore, S.C., Lin, J., Cook, N.R., Manson, J.E., Lee, I.M., and Buring, J.E. (2006) Folate, vitamin B6, multivitamin supplements, and colorectal cancer risk in women. Am J Epidemiol 163, 108–15.PubMedCrossRefGoogle Scholar
  42. 42.
    Ma, J., Stampfer, M.J., Giovannucci, E., Artigas, C., Hunter, D.J., Fuchs, C., Willett, W.C., Selhub, J., Hennekens, C.H., and Rozen, R. (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 57, 1098–102.PubMedGoogle Scholar
  43. 43.
    Van Guelpen, B., Hultdin, J., Johansson, I., Hallmans, G., Stenling, R., Riboli, E., Winkvist, A., and Palmqvist, R. (2006) Low folate levels may protect against colorectal cancer. Gut 55, 1461–66.PubMedCrossRefGoogle Scholar
  44. 44.
    Lajous, M., Lazcano-Ponce, E., Hernandez-Avila, M., Willett, W., and Romieu, I. (2006) Folate, vitamin B6, and vitamin B12 intake and the risk of breast cancer among Mexican women. Cancer Epidemiol Biomarkers Prev 15, 443–48.PubMedCrossRefGoogle Scholar
  45. 45.
    Ericson, U., Sonestedt, E., Gullberg, B., Olsson, H., and Wirfalt, E. (2007) High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmo Diet and Cancer cohort. Am J Clin Nutr 86, 434–43.PubMedGoogle Scholar
  46. 46.
    Cho, E., Holmes, M., Hankinson, S.E., and Willett, W.C. (2007) Nutrients involved in one-carbon metabolism and risk of breast cancer among premenopausal women. Cancer Epidemiol Biomarkers Prev 16, 2787–90.PubMedCrossRefGoogle Scholar
  47. 47.
    Stolzenberg-Solomon, R.Z., Chang, S.C., Leitzmann, M.F., Johnson, K.A., Johnson, C., Buys, S.S., Hoover, R.N., and Ziegler, R.G. (2006) Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr 83, 895–904.PubMedGoogle Scholar
  48. 48.
    Zhang, S., Hunter, D.J., Hankinson, S.E., Giovannucci, E.L., Rosner, B.A., Colditz, G.A., Speizer, F.E., and Willett, W.C. (1999) A prospective study of folate intake and the risk of breast cancer. JAMA 281, 1632–37.PubMedCrossRefGoogle Scholar
  49. 49.
    Sellers, T.A., Kushi, L.H., Cerhan, J.R., Vierkant, R.A., Gapstur, S.M., Vachon, C.M., Olson, J.E., Therneau, T.M., and Folsom, A.R. (2001) Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 12, 420–28.PubMedCrossRefGoogle Scholar
  50. 50.
    Rohan, T.E., Jain, M.G., Howe, G.R., and Miller, A.B. (2000) Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 92, 266–69.PubMedCrossRefGoogle Scholar
  51. 51.
    Ulrich, C.M. (2007) Folate and cancer prevention: A closer look at a complex picture. Am J Clin Nutr 86, 271–73.PubMedGoogle Scholar
  52. 52.
    Ulrich, C.M., and Potter, J.D. (2007) Folate and cancer––timing is everything. JAMA 297, 2408–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Maruti, S.S., Ulrich, C.M., and White, E. (2009) Folate and one-carbon metabolism nutrients from supplements and diet in relation to breast cancer risk. Am J Clin Nutr 89, 624–33.Google Scholar
  54. 54.
    Vollset, S.E., Igland, J., Jenab, M., Fredriksen, A., Meyer, K., Eussen, S., Gjessing, H.K., Ueland, P.M., Pera, G., Sala, N., Agudo, A., Capella, G., Del Giudice, G., Palli, D., Boeing, H. (2007) The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev 16, 2416–24.PubMedCrossRefGoogle Scholar
  55. 55.
    Slatore, C.G., Littman, A.J., Au, D.H., Satia, J.A., and White, E. (2008) Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer. Am J Respir Crit Care Med 177, 524–30.PubMedCrossRefGoogle Scholar
  56. 56.
    Stolzenberg-Solomon, R.Z., Albanes, D., Nieto, F.J., Hartman, T.J., Tangrea, J.A., Rautalahti, M., Selhub, J., Virtamo, J., and Taylor, P.R. (1999) Pancreatic cancer risk and nutrition-related methyl-group availability indicators in male smokers. J Natl Cancer Inst 91, 535–41.PubMedCrossRefGoogle Scholar
  57. 57.
    Schernhammer, E., Wolpin, B., Rifai, N., Cochrane, B., Manson, J.A., Ma, J., Giovannucci, E., Thomson, C., Stampfer, M.J., and Fuchs, C. (2007) Plasma folate, vitamin B6, vitamin B12, and homocysteine and pancreatic cancer risk in four large cohorts. Cancer Res 67, 5553–60.PubMedCrossRefGoogle Scholar
  58. 58.
    Navarro Silvera, S.A., Jain, M., Howe, G.R., Miller, A.B., and Rohan, T.E. (2006) Dietary folate consumption and risk of ovarian cancer: A prospective cohort study. Eur J Cancer Prev 15, 511–15.PubMedCrossRefGoogle Scholar
  59. 59.
    Tworoger, S.S., Hecht, J.L., Giovannucci, E., and Hankinson, S.E. (2006) Intake of folate and related nutrients in relation to risk of epithelial ovarian cancer. Am J Epidemiol 163, 1101–11.PubMedCrossRefGoogle Scholar
  60. 60.
    Kelemen, L.E., Sellers, T.A., Vierkant, R.A., Harnack, L., and Cerhan, J.R. (2004) Association of folate and alcohol with risk of ovarian cancer in a prospective study of postmenopausal women. Cancer Causes Control 15, 1085–93.PubMedCrossRefGoogle Scholar
  61. 61.
    Larsson, S.C., Giovannucci, E., and Wolk, A. (2004) Dietary folate intake and incidence of ovarian cancer: The Swedish Mammography Cohort. J Natl Cancer Inst 96, 396–402.PubMedCrossRefGoogle Scholar
  62. 62.
    Welzel, T.M., Katki, H.A., Sakoda, L.C., Evans, A.A., London, W.T., Chen, G., O’Broin, S., Shen, F.M., Lin, W.Y., and McGlynn, K.A. (2007) Blood folate levels and risk of liver damage and hepatocellular carcinoma in a prospective high-risk cohort. Cancer Epidemiol Biomarkers Prev 16, 1279–82.PubMedCrossRefGoogle Scholar
  63. 63.
    Koutros, S., Zhang, Y., Zhu, Y., Mayne, S.T., Zahm, S.H., Holford, T.R., Leaderer, B.P., Boyle, P., and Zheng, T. (2008) Nutrients contributing to one-carbon metabolism and risk of non-Hodgkin lymphoma subtypes. Am J Epidemiol 167, 287–94.PubMedCrossRefGoogle Scholar
  64. 64.
    Lim, U., Schenk, M., Kelemen, L.E., Davis, S., Cozen, W., Hartge, P., Ward, M.H., and Stolzenberg-Solomon, R. (2005) Dietary determinants of one-carbon metabolism and the risk of non-Hodgkin’s lymphoma: NCI-SEER case-control study, 1998–2000. Am J Epidemiol 162, 953–64.PubMedCrossRefGoogle Scholar
  65. 65.
    Polesel, J., Dal Maso, L., La Vecchia, C., Montella, M., Spina, M., Crispo, A., Talamini, R., and Franceschi, S. (2007) Dietary folate, alcohol consumption, and risk of non-Hodgkin lymphoma. Nutr Cancer 57, 146–50.PubMedCrossRefGoogle Scholar
  66. 66.
    Lim, U., Weinstein, S., Albanes, D., Pietinen, P., Teerenhovi, L., Taylor, P.R., Virtamo, J., and Stolzenberg-Solomon, R. (2006) Dietary factors of one-carbon metabolism in relation to non-Hodgkin lymphoma and multiple myeloma in a cohort of male smokers. Cancer Epidemiol Biomarkers Prev 15, 1109–14.PubMedCrossRefGoogle Scholar
  67. 67.
    Zhang, S.M., Hunter, D.J., Rosner, B.A., Giovannucci, E.L., Colditz, G.A., Speizer, F.E., and Willett, W.C. (2000) Intakes of fruits, vegetables, and related nutrients and the risk of non-Hodgkin’s lymphoma among women. Cancer Epidemiol Biomarkers Prev 9, 477–85.PubMedGoogle Scholar
  68. 68.
    Wang, J.T., Ma, X.C., Cheng, Y.Y., Ding, L., and Zhou, Q. (2006) A case-control study on the association between folate and cervical cancer. Zhonghua Liu Xing Bing Xue Za Zhi 27, 424–27.PubMedGoogle Scholar
  69. 69.
    VanEenwyk, J., Davis, F.G., and Bowen, P.E. (1991) Dietary and serum carotenoids and cervical intraepithelial neoplasia. Int J Cancer 48, 34–38.PubMedCrossRefGoogle Scholar
  70. 70.
    Ziegler, R.G., Jones, C.J., Brinton, L.A., Norman, S.A., Mallin, K., Levine, R.S., Lehman, H.F., Hamman, R.F., Trumble, A.C., Rosenthal, J.F. et al. (1991) Diet and the risk of in situ cervical cancer among white women in the United States. Cancer Causes Control 2, 17–29.PubMedCrossRefGoogle Scholar
  71. 71.
    Liu, T., Soong, S.J., Wilson, N.P., Craig, C.B., Cole, P., Macaluso, M., and Butterworth, C.E., Jr. (1993) A case control study of nutritional factors and cervical dysplasia. Cancer Epidemiol Biomarkers Prev 2, 525–30.PubMedGoogle Scholar
  72. 72.
    Kwasniewska, A., Charzewska, J., Tukendorf, A., and Semczuk, M. (1998) Dietary factors in women with dysplasia colli uteri associated with human papillomavirus infection. Nutr Cancer 30, 39–45.PubMedCrossRefGoogle Scholar
  73. 73.
    Brock, K.E., Berry, G., Mock, P.A., MacLennan, R., Truswell, A.S., and Brinton, L.A. (1988) Nutrients in diet and plasma and risk of in situ cervical cancer. J Natl Cancer Inst 80, 580–85.PubMedCrossRefGoogle Scholar
  74. 74.
    Hernandez, B.Y., McDuffie, K., Wilkens, L.R., Kamemoto, L., and Goodman, M.T. (2003) Diet and premalignant lesions of the cervix: Evidence of a protective role for folate, riboflavin, thiamin, and vitamin B12. Cancer Causes Control 14, 859–70.PubMedCrossRefGoogle Scholar
  75. 75.
    Kjellberg, L., Hallmans, G., Ahren, A.M., Johansson, R., Bergman, F., Wadell, G., Angstrom, T., and Dillner, J. (2000) Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection. Br J Cancer 82, 1332–38.PubMedCrossRefGoogle Scholar
  76. 76.
    Thomson, S.W., Heimburger, D.C., Cornwell, P.E., Turner, M.E., Sauberlich, H.E., Fox, L.M., and Butterworth, C.E. (2000) Correlates of total plasma homocysteine: Folic acid, copper, and cervical dysplasia. Nutrition 16, 411–16.PubMedCrossRefGoogle Scholar
  77. 77.
    Piyathilake, C.J., Macaluso, M., Brill, I., Heimburger, D.C., and Partridge, E.E. (2007) Lower red blood cell folate enhances the HPV-16-associated risk of cervical intraepithelial neoplasia. Nutrition 23, 203–10.PubMedCrossRefGoogle Scholar
  78. 78.
    Butterworth, C.E., Jr., Hatch, K.D., Macaluso, M., Cole, P., Sauberlich, H.E., Soong, S.J., Borst, M., and Baker, V.V. (1992) Folate deficiency and cervical dysplasia. JAMA 267, 528–33.PubMedCrossRefGoogle Scholar
  79. 79.
    Potischman, N., Brinton, L.A., Laiming, V.A., Reeves, W.C., Brenes, M.M., Herrero, R., Tenorio, F., de Britton, R.C., and Gaitan, E. (1991) A case-control study of serum folate levels and invasive cervical cancer. Cancer Res 51, 4785–89.PubMedGoogle Scholar
  80. 80.
    Yeo, A.S., Schiff, M.A., Montoya, G., Masuk, M., van Asselt-King, L., and Becker, T.M. (2000) Serum micronutrients and cervical dysplasia in Southwestern American Indian women. Nutr Cancer 38, 141–50.PubMedCrossRefGoogle Scholar
  81. 81.
    Weinstein, S.J., Ziegler, R.G., Frongillo, E.A., Jr., Colman, N., Sauberlich, H.E., Brinton, L.A., Hamman, R.F., Levine, R.S., Mallin, K., Stolley, P.D., and Bisogni, C.A. (2001) Low serum and red blood cell folate are moderately, but nonsignificantly associated with increased risk of invasive cervical cancer in US women. J Nutr 131, 2040–48.PubMedGoogle Scholar
  82. 82.
    Ziegler, R.G., Weinstein, S.J., and Fears, T.R. (2002) Nutritional and genetic inefficiencies in one-carbon metabolism and cervical cancer risk. J Nutr 132, 2345S–2349S.PubMedGoogle Scholar
  83. 83.
    Butterworth, C.E., Jr., Hatch, K.D., Gore, H., Mueller, H., and Krumdieck, C.L. (1982) Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 35, 73–82.PubMedGoogle Scholar
  84. 84.
    Butterworth, C.E., Jr., Hatch, K.D., Soong, S.J., Cole, P., Tamura, T., Sauberlich, H.E., Borst, M., Macaluso, M., and Baker, V. (1992) Oral folic acid supplementation for cervical dysplasia: A clinical intervention trial. Am J Obstet Gynecol 166, 803–09.PubMedGoogle Scholar
  85. 85.
    Childers, J.M., Chu, J., Voigt, L.F., Feigl, P., Tamimi, H.K., Franklin, E.W., Alberts, D.S., and Meyskens, F.L., Jr. (1995) Chemoprevention of cervical cancer with folic acid: A phase III Southwest Oncology Group Intergroup study. Cancer Epidemiol Biomarkers Prev 4, 155–59.PubMedGoogle Scholar
  86. 86.
    Zarcone, R., Bellini, P., Carfora, E., Vicinanza, G., and Raucci, F. (1996) Folic acid and cervix dysplasia. Minerva Ginecol 48, 397–400.PubMedGoogle Scholar
  87. 87.
    Thompson, J.R., Gerald, P.F., Willoughby, M.L., and Armstrong, B.K. (2001) Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: A case-control study. Lancet 358, 1935–40.PubMedCrossRefGoogle Scholar
  88. 88.
    Dockerty, J.D., Herbison, P., Skegg, D.C., and Elwood, M. (2007) Vitamin and mineral supplements in pregnancy and the risk of childhood acute lymphoblastic leukaemia: A case-control study. BMC Public Health 7, 136.PubMedCrossRefGoogle Scholar
  89. 89.
    Almadori, G., Bussu, F., Galli, J., Cadoni, G., Zappacosta, B., Persichilli, S., Minucci, A., Giardina, B., and Maurizi, M. (2005) Serum levels of folate, homocysteine, and vitamin B12 in head and neck squamous cell carcinoma and in laryngeal leukoplakia. Cancer 103, 284–92.PubMedCrossRefGoogle Scholar
  90. 90.
    Eleftheriadou, A., Chalastras, T., Ferekidou, E., Yiotakis, I., Kyriou, L., Tzagarakis, M., Ferekidis, E., and Kandiloros, D. (2006) Association between squamous cell carcinoma of the head and neck and serum folate and homocysteine. Anticancer Res 26, 2345–48.PubMedGoogle Scholar
  91. 91.
    Suzuki, T., Matsuo, K., Hirose, K., Hiraki, A., Kawase, T., Watanabe, M., Yamashita, T., Iwata, H., and Tajima, K. (2008) One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis 29, 356–62.PubMedCrossRefGoogle Scholar
  92. 92.
    Xu, W.H., Shrubsole, M.J., Xiang, Y.B., Cai, Q., Zhao, G.M., Ruan, Z.X., Cheng, J.R., Zheng, W., and Shu, X.O. (2007) Dietary folate intake, MTHFR genetic polymorphisms, and the risk of endometrial cancer among Chinese women. Cancer Epidemiol Biomarkers Prev 16, 281–87.PubMedCrossRefGoogle Scholar
  93. 93.
    McCann, S.E., Freudenheim, J.L., Marshall, J.R., Brasure, J.R., Swanson, M.K., and Graham, S. (2000) Diet in the epidemiology of endometrial cancer in western New York (United States). Cancer Causes Control 11, 965–74.PubMedCrossRefGoogle Scholar
  94. 94.
    Negri, E., La Vecchia, C., Franceschi, S., Levi, F., and Parazzini, F. (1996) Intake of selected micronutrients and the risk of endometrial carcinoma. Cancer 77, 917–23.PubMedCrossRefGoogle Scholar
  95. 95.
    Potischman, N., Swanson, C.A., Brinton, L.A., McAdams, M., Barrett, R.J., Berman, M.L., Mortel, R., Twiggs, L.B., Wilbanks, G.D., and Hoover, R.N. (1993) Dietary associations in a case-control study of endometrial cancer. Cancer Causes Control 4, 239–50.PubMedGoogle Scholar
  96. 96.
    Little, J., Sharp, L., Duthie, S., and Narayanan, S. (2003) Colon cancer and genetic variation in folate metabolism: The clinical bottom line. J Nutr 133, 3758S–3766S.PubMedGoogle Scholar
  97. 97.
    Ulrich, C. (2006) Genetic variability in folate-mediated one-carbon metabolism and cancer risk. In: Choi, S.W. and Friso, S., eds. Nutrient-Gene Interactions in Cancer. 75–91, Boca Raton, FL: Taylor & Francis Group.CrossRefGoogle Scholar
  98. 98.
    Ulrich, C.M. (2005) Nutrigenetics in cancer research–folate metabolism and colorectal cancer. J Nutr 135, 2698–702.PubMedGoogle Scholar
  99. 99.
    Nijhout, H.F., Reed, M.C., Budu, P., and Ulrich, C.M. (2004) A mathematical model of the folate cycle: New insights into folate homeostasis. J Biol Chem 279, 55008–16.PubMedCrossRefGoogle Scholar
  100. 100.
    Ulrich, C.M., Neuhouser, M.L., Liu, A.Y., Boynton, A., Gregory, G.F., 3rd., Shane, B.S., James, S.J., Reed, M.C., and Nijhout, H.F. (2008) Mathematical modeling of folate metabolism: Predicted effects of genetic polymorphisms on mechanisms and biomarkers relevant to carcinogenesis. Cancer Epidemiol Biomarkers Prev 17, 1822–31.PubMedCrossRefGoogle Scholar
  101. 101.
    Blount, B.C., Mack, M.M., Wehr, C.M., MacGregor, J.T., Hiatt, R.A., Wang, G., Wickramasinghe, S.N., Everson, R.B., and Ames, B.N. (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proc Natl Acad Sci USA 94, 3290–95.PubMedCrossRefGoogle Scholar
  102. 102.
    Quinlivan, E.P., Davis, S.R., Shelnutt, K.P., Henderson, G.N., Ghandour, H., Shane, B., Selhub, J., Bailey, L.B., Stacpoole, P.W., and Gregory, J.F., 3rd. (2005) Methylenetetrahydrofolate reductase 677C–>T polymorphism and folate status affect one-carbon incorporation into human DNA deoxynucleosides. J Nutr 135, 389–96.PubMedGoogle Scholar
  103. 103.
    Stern, L.L., Mason, J.B., Selhub, J., and Choi, S.W. (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 Epidemiol Biomarkers Prev 9, 849–53.PubMedGoogle Scholar
  104. 104.
    Davis, C.D., and Uthus, E.O. (2004) DNA methylation, cancer susceptibility, and nutrient interactions. Exp Biol Med 229, 988–95.Google Scholar
  105. 105.
    Frosst, P., Blom, H.J., Milos, R., Goyette, P., Sheppard, C.A., Matthews, R.G., Boers, G.J., den Heijer, M., Kluijtmans, L.A., van den Heuvel, L.P., and Rozen, R. (1995) A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase [letter]. Nat Genet 10, 111–13.PubMedCrossRefGoogle Scholar
  106. 106.
    Weisberg, I.S., Jacques, P.F., Selhub, J., Bostom, A.G., Chen, Z., Curtis Ellison, R., Eckfeldt, J.H., and Rozen, R. (2001) The 1298A–>C polymorphism in methylenetetrahydrofolate reductase (MTHFR): In vitro expression and association with homocysteine. Atherosclerosis 156, 409–15.PubMedCrossRefGoogle Scholar
  107. 107.
    Bailey, L.B., and Gregory, J.F., 3rd. (1999) Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: Metabolic significance, risks and impact on folate requirement. J Nutr 129, 919–22.PubMedGoogle Scholar
  108. 108.
    Ulvik, A., Ueland, P.M., Fredriksen, A., Meyer, K., Vollset, S.E., Hoff, G., and Schneede, J. (2007) Functional inference of the methylenetetrahydrofolate reductase 677 C > T and 1298A > C polymorphisms from a large-scale epidemiological study. Hum Genet 121, 57–64.PubMedCrossRefGoogle Scholar
  109. 109.
    Huang, Y., Han, S., Li, Y., Mao, Y., and Xie, Y. (2007) Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: A meta-analysis. J Hum Genet 52, 73–85.PubMedCrossRefGoogle Scholar
  110. 110.
    Hubner, R.A., and Houlston, R.S.M.T.H.F.R. (2007) C677T and colorectal cancer risk: A meta-analysis of 25 populations. Int J Cancer 120, 1027–35.PubMedCrossRefGoogle Scholar
  111. 111.
    Zintzaras, E. (2006) Methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: A meta-analysis. Clin Genet 69, 327–36.PubMedCrossRefGoogle Scholar
  112. 112.
    Mao, R., Fan, Y., Jin, Y., Bai, J., and Fu, S. (2008) Methylenetetrahydrofolate reductase gene polymorphisms and lung cancer: A meta-analysis. J Hum Genet 53, 340–48.PubMedCrossRefGoogle Scholar
  113. 113.
    Pereira, T.V., Rudnicki, M., Pereira, A.C., Pombo-de-Oliveira, M.S., and Franco, R.F. (2006) 5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: A meta-analysis. Cancer Epidemiol Biomarkers Prev 15, 1956–63.PubMedCrossRefGoogle Scholar
  114. 114.
    Zintzaras, E., Koufakis, T., Ziakas, P.D., Rodopoulou, P., Giannouli, S., and Voulgarelis, M. (2006) A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia. Eur J Epidemiol 21, 501–10.PubMedCrossRefGoogle Scholar
  115. 115.
    Boccia, S., Hung, R., Ricciardi, G., Gianfagna, F., Ebert, M.P., Fang, J.Y., Gao, C.M., Gotze, T., Graziano, F., Lacasana-Navarro, M., Lin, D., Lopez-Carrillo, L., Qiao, Y.L., Shen, H., Stolzenberg-Solomon, R., Takezaki, T., Weng, Y.R., Zhang, F.F., van Duijn, C.M., Boffetta, P., and Taioli, E. (2008) Meta- and pooled analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer risk: A huge-GSEC review. Am J Epidemiol 167, 505–16.PubMedCrossRefGoogle Scholar
  116. 116.
    Zintzaras, E. (2006) Association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with genetic susceptibility to gastric cancer: A meta-analysis. J Hum Genet 51, 618–24.PubMedCrossRefGoogle Scholar
  117. 117.
    Kaneda, S., Takeishi, K., Ayusawa, D., Shimizu, K., Seno, T., and Altman, S. (1987) Role in translation of a triple tandemly repeated sequence in the 5′-untranslated region of human thymidylate synthase mRNA. Nucleic Acids Res 15, 1259–70.PubMedCrossRefGoogle Scholar
  118. 118.
    Horie, N., Aiba, H., Oguro, K., Hojo, H., and Takeishi, K. (1995) Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 20, 191–97.PubMedCrossRefGoogle Scholar
  119. 119.
    Pullarkat, S.T., Stoehlmacher, J., Ghaderi, V., Xiong, Y.-P., Ingles, S.A., Sherrod, A., Warren, R., Tsao-Wei, D., Groshen, S., and Lenz, H.-J. (2001) Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 1, 65–70.PubMedCrossRefGoogle Scholar
  120. 120.
    Chen, J., Hunter, D.J., Stampfer, M.J., Kyte, C., Chan, W., Wetmur, J.G., Mosig, R., Selhub, J., and Ma, J. (2003) Polymorphism in the thymidylate synthase promoter enhancer region modifies the risk and survival of colorectal cancer. Cancer Epidemiol Biomarkers Prev 12, 958–62.PubMedGoogle Scholar
  121. 121.
    Ulrich, C.M., Curtin, K., Potter, J.D., Bigler, J., Caan, B., and Slattery, M.L. (2005) Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 14, 2509–16.PubMedCrossRefGoogle Scholar
  122. 122.
    Skibola, C.F., Smith, M.T., Hubbard, A., Shane, B., Roberts, A.C., Law, G.R., Rollinson, S., Roman, E., Cartwright, R.A., and Morgan, G.J. (2002) Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood 99, 3786–91.PubMedCrossRefGoogle Scholar
  123. 123.
    Mandola, M.V., Stoehlmacher, J., Muller-Weeks, S., Cesarone, G., Yu, M.C., Lenz, H.J., and Ladner, R.D. (2003) A novel single nucleotide polymorphism within the 5′ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 63, 2898–904.PubMedGoogle Scholar
  124. 124.
    Ulrich, C.M., Bigler, J., Velicer, C., Greene, E., Farin, F., and Potter, J.D. (2000) Searching expressed sequence tag databases: Discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 9, 1381–85.PubMedGoogle Scholar
  125. 125.
    Mandola, M.V., Stoehlmacher, J., Zhang, W., Groshen, S., Yu, M.C., Iqbal, S., Lenz, H.J., and Ladner, R.D.A. (2004) 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 14, 319–27.PubMedCrossRefGoogle Scholar
  126. 126.
    Ulrich, C.M., Bigler, J., Bostick, R., Fosdick, L., and Potter, J.D. (2002) Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomas. Cancer Res 62, 3361–64.PubMedGoogle Scholar
  127. 127.
    Xu, X., Liu, A.Y., and Ulrich, C.M. (2009) Folate and cancer: Epidemiological perspective. In: Bailey, L., ed. Folate in Health and Disease, 2nd Edition.Google Scholar
  128. 128.
    Liu, A.Y., and Ulrich, C.M. (2009) Genetic Variability in folate-mediated one-carbon metabolism and risk of colorectal neoplasia. In: Lindor, L., and Potter, J.D., eds. Genetic Susceptibility to Colorectal Cancer. Springer, New York, 223–42.Google Scholar
  129. 129.
    Ulrich, C.M., Nijhout, H.F., and Reed, M.C. (2006) Mathematical modeling: Epidemiology meets systems biology. Cancer Epidemiol Biomarkers Prev 15, 827–29.PubMedCrossRefGoogle Scholar
  130. 130.
    Reed, M.C., Nijhout, H.F., Neuhouser, M.L., Gregory, J.F., 3rd., Shane, B., James, S.J., Boynton, A., and Ulrich, C.M. (2006) A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism. J Nutr 136, 2653–61.PubMedGoogle Scholar
  131. 131.
    Nijhout, H.F., Reed, M., Anderson, D., Mattingly, J., James, S.J., and Ulrich, C.M. (2006) Long-range allosteric interactions between the folate and methionine cycles stabilize DNA methylation rate. Epigenetics 1, 81–87.PubMedCrossRefGoogle Scholar
  132. 132.
    Nijhout, H.F., Reed, M.C., Lam, S.L., Shane, B., Gregory, J.F., 3rd., and Ulrich, C.M. (2006) In silico experimentation with a model of hepatic mitochondrial folate metabolism. Theor Biol Med Model 3, 40.PubMedCrossRefGoogle Scholar
  133. 133.
    Kim, Y.I. (2006) Folate: A magic bullet or a double edged sword for colorectal cancer prevention? Gut 55, 1387–89.PubMedCrossRefGoogle Scholar
  134. 134.
    Kim, Y.I. (2004) Folate, colorectal carcinogenesis, and DNA methylation: Lessons from animal studies. Environ Mol Mutagen 44, 10–25.PubMedCrossRefGoogle Scholar
  135. 135.
    Song, J., Medline, A., Mason, J.B., Gallinger, S., and Kim, Y.I. (2000) Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse. Cancer Res 60, 5434–40.PubMedGoogle Scholar
  136. 136.
    Baggott, J.E., Vaughn, W.H., Juliana, M.M., Eto, I., Krumdieck, C.L., and Grubbs, C.J. (1992) Effects of folate deficiency and supplementation on methylnitrosourea-induced rat mammary tumors. J Natl Cancer Inst 84, 1740–44.PubMedCrossRefGoogle Scholar
  137. 137.
    Kotsopoulos, J., Sohn, K.J., Martin, R., Choi, M., Renlund, R., McKerlie, C., Hwang, S.W., Medline, A., and Kim, Y.I. (2003) Dietary folate deficiency suppresses N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats. Carcinogenesis 24, 937–44.PubMedCrossRefGoogle Scholar
  138. 138.
    Kotsopoulos, J., Medline, A., Renlund, R., Sohn, K.J., Martin, R., Hwang, S.W., Lu, S., Archer, M.C., and Kim, Y.I. (2005) Effects of dietary folate on the development and progression of mammary tumors in rats. Carcinogenesis 26, 1603–12.PubMedCrossRefGoogle Scholar
  139. 139.
    Cole, B.F., Baron, J.A., Sandler, R.S., Haile, R.W., Ahnen, D.J., Bresalier, R.S., McKeown-Eyssen, G., Summers, R.W., Rothstein, R.I., Burke, C.A., Snover, D.C., Church, T.R., Allen, J.I., Robertson, D.J., Beck, G.J., Bond, J.H., Byers, T., Mandel, J.S., Mott, L.A., Pearson, L.H., Barry, E.L., Rees, J.R., Marcon, N., Saibil, F., Ueland, P.M., and Greenberg, E.R. (2007) Folic acid for the prevention of colorectal adenomas: A randomized clinical trial. JAMA 297, 2351–59.PubMedCrossRefGoogle Scholar
  140. 140.
    Logan, R.F., Grainge, M.J., Shepherd, V.C., Armitage, N.C., and Muir, K.R. (2007) Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology. 134, 29–38.PubMedCrossRefGoogle Scholar
  141. 141.
    Mason, J.B., Dickstein, A., Jacques, P.F., Haggarty, P., Selhub, J., Dallal, G., and Rosenberg, I.H. (2007) A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: A hypothesis. Cancer Epidemiol Biomarkers Prev 16, 1325–29.PubMedCrossRefGoogle Scholar
  142. 142.
    Luebeck, E.G., and Moolgavkar, S.H. (2002) Multistage carcinogenesis and the incidence of colorectal cancer. Proc Natl Acad Sci USA 99, 15095–100.PubMedCrossRefGoogle Scholar
  143. 143.
    Luebeck, E.G., Moolgavkar, S.H., Liu, A.Y., Boynton, A., and Ulrich, C.M. (2008) Does folic-acid supplementation prevent or promote colorectal cancer? Results from model-based predictions. Cancer Epidemiol Biomarkers Prev 17, 1360–67.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Cornelia M. Ulrich
    • 1
    • 2
  • Xinran Xu
    • 3
  • Amy Liu
    • 1
  • Jia Chen
    • 3
  1. 1.Cancer Prevention Research ProgramFred Hutchinson Cancer Research CenterSeattleUSA
  2. 2.NCT Division of Preventive OncologyGerman Cancer Research CenterHeidelbergGermany
  3. 3.Mount Sinai School of MedicineNew YorkUSA

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