Cancer Causes & Control

, Volume 17, Issue 8, pp 1005–1016 | Cite as

Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?

  • N. T. BrocktonEmail author
Hypothesis Paper


Dietary folate has been consistently associated with reduced risk of colorectal cancer (CRC). One of the known biochemical roles of folate is donation of methyl moieties. DNA hypomethylation is an early and almost ubiquitous occurrence in tumor tissue. Therefore, it was originally suggested that adequate folate intake contributed to reduced risk of CRC by facilitating methyl-mediated silencing of oncogenes. Methylene tetrahydrofolate reductase (MTHFR) metabolizes 5,10-MTHF (important in DNA synthesis) to 5-MTHF (contributes to downstream methylation reactions by regeneration of methionine from homocysteine). A common polymorphism in the MTHFR gene (C677T) results in a thermolabile phenotype associated with increased homocysteine levels and DNA hypomethylation. Consistent with the folate/methylation hypothesis, it was originally proposed that C677T may increase risk of CRC due to hypomethylation of oncogenes. However, most subsequent studies have reported a reduced risk associated with this polymorphism. This is inconsistent with methylation as the mechanism by which folate and MTHFR genotype mediate CRC risk. The hypothesis presented here proposes that localized folate depletion combined with the effect of the C677T polymorphism on enzyme stability, impacts on the DNA synthesis pathway and accounts for the observed variation in risk associated with genotype and folate status.


Colorectal cancer Folate MTHFR Polymorphism Hypothesis 



5,10-Methylene tetrahydrofolate


5-Methyl tetrahydrofolate


Confidence Interval


Colorectal Cancer


Deoxyribonucleic acid






Flavin Adenine Dinucleotide


Familial Adenomatous Polyposis


Gas Chromatography-Mass Spectrometry


Hereditary Non-Polyposis Colorectal Cancer


Methylene tetrahydrofolate reductase


Non-Steroidal Anti-Inflammatory Drugs


Odds Ratio






Total Homocysteine



The author would like to thank Dr. A. Molloy for valuable comments and suggestions during the early preparation of this manuscript.


  1. 1.
    Parkin, DM, Pisani, P, Ferlay, J 1999Estimates of the worldwide incidence of 25 major cancers in 1990Int J Cancer80827841PubMedGoogle Scholar
  2. 2.
    WHO, W.H.O.1997Conquering suffering, enriching humanity, vol. WHO/WHR/97World Health OrganizationGenevaGoogle Scholar
  3. 3.
    Marra, G, Boland, CR 1995Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectivesJ Natl Cancer Inst8711141125PubMedGoogle Scholar
  4. 4.
    Fuchs, CS, Giovannucci, EL, Colditz, GA,  et al. 1994A prospective study of family history and the risk of colorectal cancerNew Engl J Med33116691674PubMedGoogle Scholar
  5. 5.
    Johns, LE, Houlston, RS 2001A systematic review and meta-analysis of familial colorectal cancer riskAm J Gastroenterol9629923003PubMedGoogle Scholar
  6. 6.
    Haenszel, W, Kurihara, M 1968Studies of Japanese migrants: mortality from cancer and other diseases among Japanese in the United StatesJ Natl Cancer Inst404368PubMedGoogle Scholar
  7. 7.
    Schottenfeld D, Winawer SJ (1996) Cancers of the large intestine. In: Schottenfeld D, Fraumeni Jr JF (eds) Cancer epidemiology and prevention, vol 2. Oxford University Press, New York, pp 813–840Google Scholar
  8. 8.
    Freudenheim, JL, Graham, S, Marshall, JR,  et al. 1991Folate intake and carcinogenesis of the colon and rectumInt J Epidemiol20368374PubMedGoogle Scholar
  9. 9.
    Frosst, P, Blom, HJ, Milos, R,  et al. 1995A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductaseNat Genet10111113PubMedGoogle Scholar
  10. 10.
    Botto, LD, Yang, Q 20005,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE reviewAm J Epidemiol151862877PubMedGoogle Scholar
  11. 11.
    Wilcken, B, Bamforth, F, Li, Z,  et al. 2003Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wideJ Med Genet40619625PubMedGoogle Scholar
  12. 12.
    Rady, PL, Szucs, S, Grady, J,  et al. 2002Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793AAm J Med Genet107162168PubMedGoogle Scholar
  13. 13.
    Rosenberg, N, Murata, M, Ikeda, Y,  et al. 2002The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and AfricansAm J Hum Genet70758762PubMedGoogle Scholar
  14. 14.
    Weisberg, I, Tran, P, Christensen, B, Sibani, S, Rozen, R 1998A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activityMol Genet Metab64169172PubMedGoogle Scholar
  15. 15.
    Ray, JG, Langman, LJ, Vermeulen, MJ,  et al. 2001Genetics University of Toronto Thrombophilia Study in Women (GUTTSI): genetic and other risk factors for venous thromboembolism in womenCurr Control Trials Cardiovasc Med2141149PubMedGoogle Scholar
  16. 16.
    Shi, M, Caprau, D, Romitti, P, Christensen, K, Murray, JC 2003Genotype frequencies and linkage disequilibrium in the CEPH human diversity panel for variants in folate pathway genes MTHFR, MTHFD, MTRR, RFC1, and GCP2Birth Defects Res A Clin Mol Teratol67545549PubMedGoogle Scholar
  17. 17.
    Meisel, C, Cascorbi, I, Gerloff, T,  et al. 2001Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery diseaseAtherosclerosis154651658PubMedGoogle Scholar
  18. 18.
    Pereira, AC, Schettert, IT, Morandini Filho, AA, Guerra-Shinohara, EM, Krieger, JE 2004Methylenetetrahydrofolate reductase (MTHFR) c677t gene variant modulates the homocysteine folate correlation in a mild folate-deficient populationClin Chim Acta34099105PubMedGoogle Scholar
  19. 19.
    Put, N, Gabreels, F, Stevens, E,  et al. 1998A second common mutation in the methylenetetrahydrofolate reductase (MTHFR) gene; A risk factor for neural tube defects?Faseb J123197Google Scholar
  20. 20.
    Pepe, G, Camacho Vanegas, O, Giusti, B,  et al. 1998Heterogeneity in world distribution of the thermolabile C677T mutation in 5,10-methylenetetrahydrofolate reductaseAm J Hum Genet63917920PubMedGoogle Scholar
  21. 21.
    Feinberg, AP, Vogelstein, B 1983Hypomethylation distinguishes genes of some human cancers from their normal counterpartsNature3018992PubMedGoogle Scholar
  22. 22.
    Goelz, SE, Vogelstein, B, Hamilton, SR, Feinberg, AP 1985Hypomethylation of DNA From benign and malignant human-colon neoplasmsScience228187190PubMedGoogle Scholar
  23. 23.
    Broekmans, WMR, Klopping-Ketelaars, IAA, Schuurman, C,  et al. 2000Fruits and vegetables increase plasma carotenoids and vitamins and decrease homocysteine in humansJ Nutr13015781583PubMedGoogle Scholar
  24. 24.
    Brouwer, IA, Dusseldorp, M, West, CE,  et al. 1999Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trialJ Nutr12911351139PubMedGoogle Scholar
  25. 25.
    Friso, S, Choi, SW, Girelli, D,  et al. 2002A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate statusProc Natl Acad Sci USA9956065611PubMedGoogle Scholar
  26. 26.
    Rampersaud, GC, Kauwell, GP, Hutson, AD, Cerda, JJ, Bailey, LB 2000Genomic DNA methylation decreases in response to moderate folate depletion in elderly womenAm J Clin Nutr729981003PubMedGoogle Scholar
  27. 27.
    Yi, P, Melnyk, S, Pogribna, M,  et al. 2000Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylationJ Biol Chem2752931829323PubMedGoogle Scholar
  28. 28.
    Chen, J, Giovannucci, E, Kelsey, K,  et al. 1996A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancerCancer Res5648624864PubMedGoogle Scholar
  29. 29.
    Sharp, L, Little, J 2004Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE reviewAm J Epidemiol159423443PubMedGoogle Scholar
  30. 30.
    Slattery, ML, Potter, JD, Samowitz, W, Schaffer, D, Leppert, M 1999Methylenetetrahydrofolate reductase, diet, and risk of colon cancerCancer Epidemiol Biomarkers Prev8513518PubMedGoogle Scholar
  31. 31.
    Le Marchand, L, Donlon, T, Hankin, JH,  et al. 2002B-vitamin intake, metabolic genes, and colorectal cancer risk (United States)Cancer Causes Control13239248PubMedGoogle Scholar
  32. 32.
    Ma, J, Stampfer, MJ, Christensen, B,  et al. 1999A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer riskCancer Epidemiol Biomarkers Prev8825829PubMedGoogle Scholar
  33. 33.
    Le Marchand, L, Wilkens, LR, Kolonel, LN, Henderson, BE 2005The MTHFR C677T polymorphism and colorectal cancer: the multiethnic cohort studyCancer Epidemiol Biomarkers Prev1411981203PubMedGoogle Scholar
  34. 34.
    Jiang, Q, Chen, K, Ma, X,  et al. 2005Diets, polymorphisms of methylenetetrahydrofolate reductase, and the susceptibility of colon cancer and rectal cancerCancer Detect Prev29146154PubMedGoogle Scholar
  35. 35.
    Ma, J, Stampfer, MJ, Giovannucci, E,  et al. 1997Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancerCancer Res5710981102PubMedGoogle Scholar
  36. 36.
    Das, KC, Herbert, V 1989In vitro DNA synthesis by megaloblastic bone marrow: effect of folates and cobalamins on thymidine incorporation and de novo thymidylate synthesisAm J Hematol311120PubMedGoogle Scholar
  37. 37.
    Blount, BC, Mack, MM, Wehr, CM,  et al. 1997Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damageProc Natl Acad Sci USA9432903295PubMedGoogle Scholar
  38. 38.
    Dianov, GL, Timchenko, TV, Sinitsina, OI,  et al. 1991Repair of uracil residues closely spaced on the opposite strands of plasmid DNA results in double-strand break and deletion formationMol Gen Genet225448452PubMedGoogle Scholar
  39. 39.
    Quinlivan, EP, Davis, SR, Shelnutt, KP,  et al. 2005Methylenetetrahydrofolate reductase 677C→T polymorphism and folate status affect one-carbon incorporation into human DNA deoxynucleosidesJ Nutr135389396PubMedGoogle Scholar
  40. 40.
    Ulrich, CM, Bigler, J, Bostick, R, Fosdick, L, Potter, JD 2002Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomasCancer Res6233613364PubMedGoogle Scholar
  41. 41.
    Kapiszewska, M, Kalemba, M, Wojciech, U, Milewicz, T 2005Uracil misincorporation into DNA of leukocytes of young women with positive folate balance depends on plasma vitamin B12 concentrations and methylenetetrahydrofolate reductase polymorphisms. A pilot studyJ Nutr Biochem16467478PubMedGoogle Scholar
  42. 42.
    Guenther, BD, Sheppard, CA, Tran, P,  et al. 1999The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemiaNat Struct Biol6359365PubMedGoogle Scholar
  43. 43.
    Yamada, K, Chen, Z, Rozen, R, Matthews, RG 2001Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductaseProc Natl Acad Sci USA981485314858PubMedGoogle Scholar
  44. 44.
    Girelli, D, Friso, S, Trabetti, E,  et al. 1998Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease: evidence for an important genetic-environmental interactionBlood9141584163PubMedGoogle Scholar
  45. 45.
    Kimura, M, Umegaki, K, Higuchi, M, Thomas, P, Fenech, M 2004Methylenetetrahydrofolate reductase C677T polymorphism, folic acid and riboflavin are important determinants of genome stability in cultured human lymphocytesJ Nutr1344856PubMedGoogle Scholar
  46. 46.
    Stern, LL, Bagley, PJ, Rosenberg, IH, Selhub, J 2000Conversion of 5-formyltetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylenetetrahydrofolate reductase geneJ Nutr13022382242PubMedGoogle Scholar
  47. 47.
    Crott, JW, Mashiyama, ST, Ames, BN, Fenech, MF 2001Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into primary human lymphocyte DNA in vitroCarcinogenesis2210191025PubMedGoogle Scholar
  48. 48.
    Narayanan, S, McConnell, J, Little, J,  et al. 2004Associations between two common variants C677T and A1298C in the methylenetetrahydrofolate reductase gene and measures of folate metabolism and DNA stability (strand breaks, misincorporated uracil, and DNA methylation status) in human lymphocytes in vivoCancer Epidemiol Biomarkers Prev1314361443PubMedGoogle Scholar
  49. 49.
    Kim, Y, Pogribny, IP, Basnakian, AG,  et al. 1997Folate deficiency in rats induces DNA strand braks and hypomethylation within the p53 tumour supressor geneAm J Clin Nutr654652PubMedGoogle Scholar
  50. 50.
    Mashiyama, ST, Courtemanche, C, Elson-Schwab, I,  et al. 2004Uracil in DNA, determined by an improved assay, is increased when deoxynucleosides are added to folate-deficient cultured human lymphocytesAnal Biochem3305869PubMedGoogle Scholar
  51. 51.
    Molloy, AM, Mills, JL, Kirke, PN,  et al. 1998Whole-blood folate values in subjects with different methylenetetrahydrofolate reductase genotypes: differences between the radioassay and microbiological assaysClin Chem44186188PubMedGoogle Scholar
  52. 52.
    Thorpe, SJ, Sands, D, Heath, AB,  et al. 2004An International Standard for whole blood folate: evaluation of a lyophilised haemolysate in an international collaborative studyClin Chem Lab Med42533539PubMedGoogle Scholar
  53. 53.
    Weisberg, IS, Jacques, PF, Selhub, J,  et al. 2001The 1298A→C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteineAtherosclerosis156409415PubMedGoogle Scholar
  54. 54.
    Chango, A, Boisson, F, Barbe, F,  et al. 2000The effect of 677C→T and 1298A→C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjectsBr J Nutr83593596PubMedGoogle Scholar
  55. 55.
    Friedman, G, Goldschmidt, N, Friedlander, Y,  et al. 1999A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrationsJ Nutr12916561661PubMedGoogle Scholar
  56. 56.
    Chen, J, Ma, J, Stampfer, MJ,  et al. 2002Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancerPharmacogenetics12339342PubMedGoogle Scholar
  57. 57.
    Curtin, K, Bigler, J, Slattery, ML,  et al. 2004MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancerCancer Epidemiol Biomarkers Prev13285292PubMedGoogle Scholar
  58. 58.
    Keku, T, Millikan, R, Worley, K,  et al. 20025,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whitesCancer Epidemiol Biomarkers Prev1116111621PubMedGoogle Scholar
  59. 59.
    Sharp, L, Little, J, Brockton, NT,  et al. 2002Intake of folate and related micronutrients, genetic polymorphisms in MTHFR and colorectal cancer: a population-based case–control study in ScotlandJ Nutr1323542S3542SGoogle Scholar
  60. 60.
    Robien, K, Ulrich, CM 20035,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireviewAm J Epidemiol157571582PubMedGoogle Scholar
  61. 61.
    Isotalo, PA, Wells, GA, Donnelly, JG 2000Neonatal and fetal methylenetetrahydrofolate reductase genetic polymorphisms: an examination of C677T and A1298C mutationsAm J Human Genet67986990Google Scholar
  62. 62.
    Zetterberg, H, Regland, B, Palmer, M,  et al. 2002Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryosEur J Hum Genet10113118PubMedGoogle Scholar
  63. 63.
    Volcik, KA, Blanton, SH, Northrup, H 2001Examinations of methylenetetrahydrofolate reductase C677T and A1298C mutations–and in utero viabilityAm J Hum Genet6911501153PubMedGoogle Scholar
  64. 64.
    Hanson, NQ, Aras, O, Yang, F, Tsai, MY 2001C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular diseaseClin Chem47661666PubMedGoogle Scholar
  65. 65.
    Ogino, S, Wilson, RB 2003Genotype and haplotype distributions of MTHFR677C>T and 1298A>C single nucleotide polymorphisms: a meta-analysisJ Hum Genet4817PubMedGoogle Scholar
  66. 66.
    Chen, J, Gammon, MD, Chan, W,  et al. 2005One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancerCancer Res6516061614PubMedGoogle Scholar
  67. 67.
    Johanning, GL, Heimburger, DC, Piyathilake, CJ 2002DNA methylation and diet in cancerJ Nutr1323814S3818SPubMedGoogle Scholar
  68. 68.
    Meenan, J, O’Hallinan, E, Lynch, S,  et al. 1996Folate status of gastrointestinal epithelial cells is not predicted by serum and red cell folate values in replete subjectsGut38410413PubMedGoogle Scholar
  69. 69.
    Meenan, J, O’Hallinan, E, Scott, J, Weir, DG 1997Epithelial cell folate depletion occurs in neoplastic but not adjacent normal colon mucosaGastroenterology1121168Google Scholar
  70. 70.
    Weir, DG, Scott, JM 1998Colonic mucosal folate concentrations and their association with colorectal cancerAm J Clin Nutr68763764PubMedGoogle Scholar
  71. 71.
    Kim, YI, Fawaz, K, Knox, T,  et al. 1998Colonic mucosal concentrations of folate correlate well with blood measurements of folate status in persons with colorectal polypsAm J Clin Nutr68866872PubMedGoogle Scholar
  72. 72.
    Piyathilake, CJ, Johanning, GL, Macaluso, M,  et al. 2000Localized folate and vitamin B-12 deficiency in squamous cell lung cancer is associated with global DNA hypomethylationNutr Cancer3799107PubMedGoogle Scholar
  73. 73.
    Piyathilake, CJ, Macaluso, M, Hine, RJ, Richards, EW, Krumdieck, CL 1994Local and systemic effects of cigarette smoking on folate and vitamin B-12Am J Clin Nutr60559566PubMedGoogle Scholar
  74. 74.
    Ross, JF, Chaudhuri, PK, Ratnam, M 1994Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell linesPhysiol Clin Impl Cancer7324322443Google Scholar
  75. 75.
    Cravo, ML, Albuquerque, CM, Salazar Sousa, L,  et al. 1998Microsatellite instability in non-neoplastic mucosa of patients with ulcerative colitis: effect of folate supplementationAm J Gastroenterol9320602064PubMedGoogle Scholar
  76. 76.
    Tomkins, A 2003Assessing micronutrient status in the presence of inflammationJ Nutr1331649S1655SPubMedGoogle Scholar
  77. 77.
    Coussens, LM, Werb, Z 2002Inflammation and cancerNature420860867PubMedGoogle Scholar
  78. 78.
    Erlinger, TP, Platz, EA, Rifai, N, Helzlsouer, KJ 2004C-reactive protein and the risk of incident colorectal cancerJama291585590PubMedGoogle Scholar
  79. 79.
    Suh, JR, Herbig, AK, Stover, PJ 2001New perspectives on folate catabolismAnnu Rev Nutr21255282PubMedGoogle Scholar
  80. 80.
    Fuchs, D, Jaeger, M, Widner, B,  et al. 2001Is hyperhomocysteinemia due to the oxidative depletion of folate rather than to insufficient dietary intake?Clin Chem Lab Med39691694PubMedGoogle Scholar
  81. 81.
    Weiss, HA, Forman, D 1996Aspirin, non-steroidal anti-inflammatory drugs and protection from colorectal cancer: a review of the epidemiological evidenceScand J GastroenterolSuppl 220137141Google Scholar
  82. 82.
    IARC Working Group1997IARC Handbook of cancer prevention, volume 1: non-steroidal anti-inflammatory drugsIARCLyonGoogle Scholar
  83. 83.
    Smith, ML, Hawcroft, G, Hull, MA 2000The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of actionEur J Cancer36664674PubMedGoogle Scholar
  84. 84.
    Winawer, SJ, Fletcher, RH, Miller, L,  et al. 1997Colorectal cancer screening: clinical guidelines and rationaleGastroenterology112594642PubMedGoogle Scholar
  85. 85.
    Morson, BC 1984The evolution of colorectal carcinomaClin Radiol35425431PubMedGoogle Scholar
  86. 86.
    Foutch, PG, Mai, H, Pardy, K,  et al. 1991Flexible sigmoidoscopy may be ineffective for secondary prevention of colorectal cancer in asymptomatic, average-risk menDig Dis Sci36924928PubMedGoogle Scholar
  87. 87.
    Rex, DK, Lehman, GA, Ulbright, TM,  et al. 1993Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family historyAm J Gastroenterol88825831PubMedGoogle Scholar
  88. 88.
    Villavicencio, RT, Rex, DK 2000Colonic adenomas: prevalence and incidence rates, growth rates, and miss rates at colonoscopySemin Gastrointest Dis11185193PubMedGoogle Scholar
  89. 89.
    Rex, DK 2000Colonoscopic withdrawal technique is associated with adenoma miss ratesGastrointest Endosc513336PubMedGoogle Scholar
  90. 90.
    Giovannucci, E 2004Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studiesJ Nutr1342475S2481SPubMedGoogle Scholar
  91. 91.
    Mason, JB, Choi, SW 2005Effects of alcohol on folate metabolism: implications for carcinogenesisAlcohol35235241PubMedGoogle Scholar
  92. 92.
    Homann, N, Tillonen, J, Salaspuro, M 2000Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiencyInt J Cancer86169173PubMedGoogle Scholar
  93. 93.
    Singh, NP, Khan, A 1995Acetaldehyde: genotoxicity and cytotoxicity in human lymphocytesMutat Res337917PubMedGoogle Scholar
  94. 94.
    Shaw, S, Jayatilleke, E, Herbert, V, Colman, N 1989Cleavage of folates during ethanol metabolism. Role of acetaldehyde/xanthine oxidase-generated superoxideBiochem J257277280PubMedGoogle Scholar
  95. 95.
    Halsted, CH, Villanueva, JA, Devlin, AM, Chandler, CJ 2002Metabolic interactions of alcohol and folateJ Nutr1322367S2372SPubMedGoogle Scholar
  96. 96.
    Giovannucci, E, Chen, J, Smith-Warner, SA,  et al. 2003Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomasCancer Epidemiol Biomarkers Prev12970979PubMedGoogle Scholar
  97. 97.
    Levine, AJ, Siegmund, KD, Ervin, CM,  et al. 2000The methylenetetrahydrofolate reductase 677C→T polymorphism and distal colorectal adenoma riskCancer Epidemiol Biomarkers Prev9657663PubMedGoogle Scholar
  98. 98.
    Counts, JL, Goodman, JI 1994Hypomethylation of DNA: an epigenetic mechanism involved in tumor promotionMol Carcinog11185188PubMedGoogle Scholar
  99. 99.
    Ulrich, CM, Curtin, K, Samowitz, W,  et al. 2005MTHFR variants reduce the risk of G:C→A:T transition mutations within the p53 tumor suppressor gene in colon tumorsJ Nutr13524622467PubMedGoogle Scholar
  100. 100.
    Coulondre, C, Miller, JH, Farabaugh, PJ, Gilbert, W 1978Molecular basis of base substitution hotspots in Escherichia coli Nature274775780PubMedGoogle Scholar
  101. 101.
    James, SJ, Pogribny, IP, Pogribna, M,  et al. 2003Mechanisms of DNA damage, DNA hypomethylation, and tumor progression in the folate/methyl-deficient rat model of hepatocarcinogenesisJ Nutr1333740S3747SPubMedGoogle Scholar
  102. 102.
    Bariol, C, Suter, C, Cheong, K,  et al. 2003The relationship between hypomethylation and CpG island methylation in colorectal neoplasiaAm J Pathol16213611371PubMedGoogle Scholar
  103. 103.
    Gloria, L, Cravo, M, Pinto, A,  et al. 1996DNA hypomethylation and proliferative activity are increased in the rectal mucosa of patients with long-standing ulcerative colitisCancer7823002306PubMedGoogle Scholar
  104. 104.
    Kim, YI 2004Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studiesEnviron Mol Mutagen441025PubMedGoogle Scholar
  105. 105.
    Kim, YI 2004Will mandatory folic acid fortification prevent or promote cancer?Am J Clin Nutr8011231128PubMedGoogle Scholar
  106. 106.
    Fletcher, O, Kessling, AM 1998MTHFR association with arteriosclerotic vascular disease?Human Genet1031121Google Scholar
  107. 107.
    Klerk, M, Verhoef, P, Clarke, R,  et al. 2002MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysisJama28820232031PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  1. 1.University of Dundee, Maternal and Child Health Sciences, Ninewells HospitalDundeeUK

Personalised recommendations