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Vitamin and Carcinogenesis Program, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
Collectively, the evidence from epidemiologic, animal and human studies strongly suggests that folate status modulates the risk of developing cancers in selected tissues, the most notable of which is the colorectum. Folate depletion appears to enhance carcinogenesis whereas folate supplementation above what is presently considered to be the basal requirement appears to convey a protective effect. The means by which this modulation of cancer risk is mediated is not known with certainty, but there are several plausible mechanisms which have been described. Folate plays a major role in the formation of S-adenosylmethionine, the universal methyl donor, as well as in the formation of purine and thymidine synthesis for DNA and RNA. Therefore, most mechanistic studies performed to date have focused on alterations in DNA methylation, disruption of DNA integrity and disruption of DNA repair, all of which have been observed with folate depletion. These aberrations in DNA are believed to enhance carcinogenesis by altering the expression of critical tumor suppressor genes and proto-oncogenes. Recently, the role of a common polymorphism of the methylenetetrahydrofolate reductase gene has been highlighted as well. This review presents those mechanisms which are the most likely candidates to explain folate’s effects and it proposes an integrated scheme to explain how these mechanisms might interact.
KEY WORDS: • folate • carcinogenesis • DNA methylation • DNA integrity • MTHFR gene
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M. P Hannon-Fletcher, N. C Armstrong, J. M Scott, K. Pentieva, I. Bradbury, M. Ward, J. Strain, A. A Dunn, A. M Molloy, M. A Kerr, et al. Determining bioavailability of food folates in a controlled intervention study Am. J. Clinical Nutrition, October 1, 2004; 80(4): 911 - 918. [Abstract] [Full Text] [PDF]
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 C. Courtemanche, I. Elson-Schwab, S. T. Mashiyama, N. Kerry, and B. N. Ames Folate Deficiency Inhibits the Proliferation of Primary Human CD8+ T Lymphocytes In Vitro J. Immunol., September 1, 2004; 173(5): 3186 - 3192. [Abstract] [Full Text] [PDF]
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G. Zaza, W. Yang, L. Kager, M. Cheok, J. Downing, C.-H. Pui, C. Cheng, M. V. Relling, and W. E. Evans Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis Blood, September 1, 2004; 104(5): 1435 - 1441. [Abstract] [Full Text] [PDF]
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D. C. Cabelof, J. J. Raffoul, J. Nakamura, D. Kapoor, H. Abdalla, and A. R. Heydari Imbalanced Base Excision Repair in Response to Folate Deficiency Is Accelerated by Polymerase {beta} Haploinsufficiency J. Biol. Chem., August 27, 2004; 279(35): 36504 - 36513. [Abstract] [Full Text] [PDF]
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R. Saffroy, P. Pham, F. Chiappini, M. Gross-Goupil, L. Castera, D. Azoulay, A. Barrier, D. Samuel, B. Debuire, and A. Lemoine The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis Carcinogenesis, August 1, 2004; 25(8): 1443 - 1448. [Abstract] [Full Text] [PDF]
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C. A. Perry, S. A. Renna, E. Khitun, M. Ortiz, D. J. Moriarty, and M. A. Caudill Ethnicity and Race Influence the Folate Status Response to Controlled Folate Intakes in Young Women J. Nutr., July 1, 2004; 134(7): 1786 - 1792. [Abstract] [Full Text]
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M. E. Martinez, S. M Henning, and D. S Alberts Folate and colorectal neoplasia: relation between plasma and dietary markers of folate and adenoma recurrence Am. J. Clinical Nutrition, April 1, 2004; 79(4): 691 - 697. [Abstract] [Full Text] [PDF]
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 K. Robien, M. M. Schubert, B. Bruemmer, M. E. Lloid, J. D. Potter, and C. M. Ulrich Predictors of Oral Mucositis in Patients Receiving Hematopoietic Cell Transplants for Chronic Myelogenous Leukemia J. Clin. Oncol., April 1, 2004; 22(7): 1268 - 1275. [Abstract] [Full Text] [PDF]
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S. C. Larsson, E. Giovannucci, and A. Wolk Dietary Folate Intake and Incidence of Ovarian Cancer: The Swedish Mammography Cohort J Natl Cancer Inst, March 3, 2004; 96(5): 396 - 402. [Abstract] [Full Text] [PDF]
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K. Pentieva, H. McNulty, R. Reichert, M. Ward, J. J. Strain, D. J. McKillop, J. M. McPartlin, E. Connolly, A. Molloy, K. Kramer, et al. The Short-Term Bioavailabilities of [6S]-5-Methyltetrahydrofolate and Folic Acid Are Equivalent in Men J. Nutr., March 1, 2004; 134(3): 580 - 585. [Abstract] [Full Text] [PDF]
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K. Curtin, J. Bigler, M. L. Slattery, B. Caan, J. D. Potter, and C. M. Ulrich MTHFR C677T and A1298C Polymorphisms: Diet, Estrogen, and Risk of Colon Cancer Cancer Epidemiol. Biomarkers Prev., February 1, 2004; 13(2): 285 - 292. [Abstract] [Full Text] [PDF]
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C. M. Pfeiffer, Z. Fazili, L. McCoy, M. Zhang, and E. W. Gunter Determination of Folate Vitamers in Human Serum by Stable-Isotope-Dilution Tandem Mass Spectrometry and Comparison with Radioassay and Microbiologic Assay Clin. Chem., February 1, 2004; 50(2): 423 - 432. [Abstract] [Full Text] [PDF]
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E. L. Goode, J. D. Potter, J. Bigler, and C. M. Ulrich Methionine Synthase D919G Polymorphism, Folate Metabolism, and Colorectal Adenoma Risk Cancer Epidemiol. Biomarkers Prev., January 1, 2004; 13(1): 157 - 162. [Abstract] [Full Text] [PDF]
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 E. Odin, Y. Wettergren, S. Nilsson, R. Willen, G. Carlsson, C. P. Spears, L. Larsson, and B. Gustavsson Altered Gene Expression of Folate Enzymes in Adjacent Mucosa Is Associated with Outcome of Colorectal Cancer Patients Clin. Cancer Res., December 1, 2003; 9(16): 6012 - 6019. [Abstract] [Full Text] [PDF]
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J. Carrier, A. Medline, K.-J. Sohn, M. Choi, R. Martin, S. W. Hwang, and Y.-I. Kim Effects of Dietary Folate on Ulcerative Colitis-Associated Colorectal Carcinogenesis in the Interleukin 2- and {beta}2-Microglobulin-deficient Mice Cancer Epidemiol. Biomarkers Prev., November 1, 2003; 12(11): 1262 - 1267. [Abstract] [Full Text]
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A. Yokoyama, T. Yokoyama, T. Muramatsu, T. Omori, S. Matsushita, S. Higuchi, K. Maruyama, and H. Ishii Macrocytosis, a new predictor for esophageal squamous cell carcinoma in Japanese alcoholic men Carcinogenesis, November 1, 2003; 24(11): 1773 - 1778. [Abstract] [Full Text] [PDF]
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L. B. Bailey Folate, Methyl-Related Nutrients, Alcohol, and the MTHFR 677C->T Polymorphism Affect Cancer Risk: Intake Recommendations J. Nutr., November 1, 2003; 133(11): 3748S - 3753. [Abstract] [Full Text] [PDF]
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H. Shen, Q. Wei, P. C. Pillow, C. I. Amos, W. K. Hong, and M. R. Spitz Dietary Folate Intake and Lung Cancer Risk in Former Smokers: A Case-Control Analysis Cancer Epidemiol. Biomarkers Prev., October 1, 2003; 12(10): 980 - 986. [Abstract] [Full Text] [PDF]
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M. van Rijnsoever, H. Elsaleh, D. Joseph, K. McCaul, and B. Iacopetta CpG Island Methylator Phenotype Is an Independent Predictor of Survival Benefit from 5-Fluorouracil in Stage III Colorectal Cancer Clin. Cancer Res., August 1, 2003; 9(8): 2898 - 2903. [Abstract] [Full Text] [PDF]
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A. Zijno, C. Andreoli, P. Leopardi, F. Marcon, S. Rossi, S. Caiola, A. Verdina, R. Galati, A. Cafolla, and R. Crebelli Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects Carcinogenesis, June 1, 2003; 24(6): 1097 - 1103. [Abstract] [Full Text] [PDF]
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L. B. Bailey, G. C. Rampersaud, and G. P. A. Kauwell Folic Acid Supplements and Fortification Affect the Risk for Neural Tube Defects, Vascular Disease and Cancer: Evolving Science, J. Nutr., June 1, 2003; 133(6): 1961S - 1968. [Abstract] [Full Text] [PDF]
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 J. Lokk News and Views on Folate and Elderly Persons J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2003; 58(4): M354 - 361. [Abstract] [Full Text] [PDF]
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K. Robien and C. M. Ulrich 5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Leukemia Risk: A HuGE Minireview Am. J. Epidemiol., April 1, 2003; 157(7): 571 - 582. [Abstract] [Full Text] [PDF]
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S.-W. Choi, S. Friso, G. G. Dolnikowski, P. J. Bagley, A. N. Edmondson, D. E. Smith, and J. B. Mason Biochemical and Molecular Aberrations in the Rat Colon Due to Folate Depletion Are Age-Specific J. Nutr., April 1, 2003; 133(4): 1206 - 1212. [Abstract] [Full Text] [PDF]
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J. B. Mason Biomarkers of Nutrient Exposure and Status in One-Carbon (Methyl) Metabolism J. Nutr., March 1, 2003; 133(3): 941S - 947. [Abstract] [Full Text] [PDF]
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H. S. Feigelson, C. R. Jonas, A. S. Robertson, M. L. McCullough, M. J. Thun, and E. E. Calle Alcohol, Folate, Methionine, and Risk of Incident Breast Cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort Cancer Epidemiol. Biomarkers Prev., February 1, 2003; 12(2): 161 - 164. [Abstract] [Full Text] [PDF]
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B. Diergaarde, W. L. van Geloof, G. N.P. van Muijen, F. J. Kok, and E. Kampman Dietary factors and the occurrence of truncating APC mutations in sporadic colon carcinomas: a Dutch population-based study Carcinogenesis, February 1, 2003; 24(2): 283 - 290. [Abstract] [Full Text] [PDF]
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G. C. Rampersaud, G. P.A. Kauwell, and L. B. Bailey Folate: A Key to Optimizing Health and Reducing Disease Risk in the Elderly J. Am. Coll. Nutr., February 1, 2003; 22(1): 1 - 8. [Abstract] [Full Text] [PDF]
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T. Marugame, E. Tsuji, C. Kiyohara, H. Eguchi, T. Oda, K. Shinchi, and S. Kono Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas Int. J. Epidemiol., February 1, 2003; 32(1): 64 - 66. [Abstract] [Full Text] [PDF]
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