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The methylenetetrahydrofolate reductase (MTHFR) gene in colorectal cancer

Role in tumor development and significance of allelic loss in tumor progression

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Abstract

Background and Aim: Folate deficiency predisposes to sporadic colorectal cancer (CRC). Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme and a polymorphism at position 677 (C677T), is associated with reduced enzyme activity. We investigated whether this functional polymorphism modulates the risk of developing CRC.

Methods: This was a retrospective case-control study, 136 unselected cases of sporadic CRC and 848 normal population controls were genotyped for the MTHFR C677T polymorphism. Tumor tissue was genotyped to assess loss of heterozygosity (LOH).

Results:MTHFR CT heterozygotes had a significantly increased risk of developing CRC (53.7% of CRC cases vs 38.4% of controls), odds ratio 1.86 (95% CI 1.3–2.7, p<0.005). No increased cancer risk was observed in TT homozygotes. The MTHFR ‘T’ allele frequency was significantly higher in the cancer group (0.3713) as compared to controls (0.2900, p<0.008). LOH at the MTHFR locus was observed in 18% of informative cancers, with exclusive loss of the variant ‘T’ allele, in all cases.

Conclusion: In this study of a homogenous northern European population, MTHFR CT heterozygotes had an almost two-fold increased risk of developing sporadic CRC. The exclusive pattern of MTHFR allele loss in cases of LOH, suggest that functional MTHFR activity within a tumor might play an important role in the survival and progression of a colonic neoplasm.

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References

  1. Giovannucci E, Rimm E, Ascherio A, Stampfer M, Colditz G, Willett W. Alcohol, low-methionine low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995;87:265–273.

    Article  PubMed  CAS  Google Scholar 

  2. Giovannucci E, Stampfer M, Colditz G, et al. Folate, methionine and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;6685:875–884.

    Article  Google Scholar 

  3. Ferraroni M, LaVecchio C, D’Avanzo B, Negri E, Franceschi S, Decarli A. Selected micronutrient intake and the risk of colorectal cancer. Br J Cancer 1994;70:1150–1155.

    PubMed  CAS  Google Scholar 

  4. Baron J, Sandler R, Haile R, Mandel J, Mott L, Greenberg E. Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas. J Natl Cancer Inst 1998;90:57–62.

    Article  PubMed  CAS  Google Scholar 

  5. Giovannucci E, Stampfer M, Colditz G, et al. Multivitamin use, folate, and colon cancer in women in the Nurses’ Health Study. Ann Int Med 1998;129:517–524.

    PubMed  CAS  Google Scholar 

  6. Gyde S, Prior P, Allan R, et al. Colorectal cancer in ulcerative colitis—a cohort study of primary referrals from three centres. Gut 1988;29:206–217.

    Article  PubMed  CAS  Google Scholar 

  7. Ekbom A, Helmick C, Zack M, Adami H. Ulcerative colitis and colorectal cancer: a population-based study. N Engl J Med 1990;323:1228–1233.

    Article  PubMed  CAS  Google Scholar 

  8. Lashner B, Heidenreich P, Su G, Kano S, Hanauer S. The effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis: a case-control study. Gastroenterology 1989;97:255–259.

    PubMed  CAS  Google Scholar 

  9. Kim I, Pogribny I, Basnakin A, et al. Folate deficiency in rats induces DNA strand breaks and hypomethylation within p53 tumor suppressor gene. Am J Clin Nutr 1997;65:46–52.

    PubMed  CAS  Google Scholar 

  10. Fearon E, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759–767.

    Article  PubMed  CAS  Google Scholar 

  11. Pogribny I, Muskhelishvili L, Miller B, James S. Presence and consequence of uracil in preneoplastic DNA from folate/methyl-deficient rats. Carcinogenesis 1997;18:2071–2076.

    Article  PubMed  CAS  Google Scholar 

  12. James S, Miller B, Basnakian A, Pogribny I, Pogribna M, Muskhelishvili L. Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats. Carcinogenesis 1997;18:287–293.

    Article  PubMed  CAS  Google Scholar 

  13. Blount B, Mack M, Wehr C, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci 1997;94:3290–3295.

    Article  PubMed  CAS  Google Scholar 

  14. Frosst P, Blom H, Milos R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111–113.

    Article  PubMed  CAS  Google Scholar 

  15. Ma J, Stampfer M, Selhub J, et al. Methylenetetrahydrofolate reductase polymorphisms, plasma folate, homocysteine and risk of myocardial infarction in US physicians. Circulation 1996;94:2410–2416.

    PubMed  CAS  Google Scholar 

  16. Molloy A, Daly S, Mills J, et al. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendation. Lancet 1997;349((9065)):1591–1593.

    Article  PubMed  CAS  Google Scholar 

  17. Stern L, Mason J, Selhub J, Choi S. Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals whho are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev 2000;9:849–853.

    PubMed  CAS  Google Scholar 

  18. van der Put N, Steegers-Theunissen R, Frosst P, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995;346:1070–1071.

    Article  PubMed  Google Scholar 

  19. Kang S, Wong P, Malinow M. Hyperhomocysteinaemia as a risk factor for occlusive vascular disease. Ann Rev Nutr 1992;12:279–98.

    Article  CAS  Google Scholar 

  20. Adams M, Smith P, Martin D, Thompson J, Lodwick D, Samana N. Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. Quart J Med 1996;89:437–444.

    CAS  Google Scholar 

  21. Ulrich C, Kampmann E, Bigler J, et al. Colorectal Adenomas and the C677T MTHFR polymorphism: Evidence for gene-Environment Interaction. Cancer, Epidemiol, Biomark, Prev 1999;8:659–668.

    CAS  Google Scholar 

  22. Marugame T, Tsuji E, Inoue H, et al. Methylenetetrahydrofolate reductase polymorphism and the risk of colorectal adenomas. Cancer Lett 2000;151:181–186.

    Article  PubMed  CAS  Google Scholar 

  23. Chen J, Giovannucci E, Hankinson S, et al. A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma. Carcinogenesis 1998;19(12):2129–32.

    Article  PubMed  CAS  Google Scholar 

  24. Slattery M, Potter J, Samomitz W, Shaffer D, Leppert M. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 1999;8(6):513–518.

    PubMed  CAS  Google Scholar 

  25. Chen J, Giovannucci E, Kelsey K, et al. A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 1996;56(21):4862–4.

    PubMed  CAS  Google Scholar 

  26. Ma J, Stampfer M, Giovannucci E, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 1997;57(6):1098–1102.

    PubMed  CAS  Google Scholar 

  27. Esteller M, Garcia A, Matrinez-Palones J, Xercavins J, Raventos J. Germ line polymorphisms in cytochrome-P450 1A1 (C4887 CYPIAI) and methylenetatrahydrofolate reductase (MTHFR) genes and endometrial cancer susceptibility. Carcinogenesis 1997;18(12):2307–2311.

    Article  PubMed  CAS  Google Scholar 

  28. Di Vinci A, Infusini E, Peveri C, Risio M, Rossini FP, Giaretti W. Deletions at chromosome 1p by fluorescence in situ hybridisation are an early event in human colorectal tumorigenesis. Gastroenterology 1996;111:102–107.

    Article  PubMed  Google Scholar 

  29. Viel A, Dall’ Agnese L, Simone F, et al. Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas. Br J Cancer 1997;75(8):1105–1110.

    PubMed  CAS  Google Scholar 

  30. Pereira P, Stanton V, Jothy S, Tomlinson I, Foulkes W, Rozen R. Loss of heterozygosity of methylenetetrahydrofolate reductase in colon carcinomas. Oncol Rep 1999;6(3):597–599.

    PubMed  CAS  Google Scholar 

  31. Mills J, Kirke P, Molloy A, et al. Methylenetetrahydrofolate reductase thermolabile variant and oral clefts. Am J Med Genet 1999;86:71–74.

    Article  PubMed  CAS  Google Scholar 

  32. Impraim C, Saiki R, Erlich H, Tephtz R. Analysis of DNA extracted from formalin-fixed, paraffin-embedded tissues by enzymatic amplification and hybridisation with sequence-specific oligonucleotides. Biochem Bio Res Comm 1987;142:710–716.

    Article  CAS  Google Scholar 

  33. Raymond M, Rousset F. GENEPOP (version 1.2): population genetics software for exact tests and ecumenicism. J Heredity 1995;86:248–249.

    Google Scholar 

  34. Djurhuus D, Svardal A, Mansoor M, Usland P. Modulation of glutathione content and the effect on methionine auxotrophy and cellular distribution of homocysteine and cysteine in mouse cell lines. Carcinogenesis 1991;12:241–247.

    Article  PubMed  CAS  Google Scholar 

  35. van der Put N, Gabreels F, Stevens E, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk for neural tube defects. Am J Hum Genet 1998;62:1044–1051.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology and Clinical Medicine, St. James’s Hospital and Trinity College, Dublin

    Barbara M. Ryan, Ross McManus, Qamrul Arfin, Dermot Kelleher & Donald G. Weir

  2. Department of Ψ Biochemistry, Trinity College, Dublin, Ireland

    Anne M. Molloy & John M. Scott

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  1. Barbara M. Ryan
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  2. Anne M. Molloy
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Correspondence to Barbara M. Ryan.

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Ryan, B.M., Molloy, A.M., McManus, R. et al. The methylenetetrahydrofolate reductase (MTHFR) gene in colorectal cancer. Int J Gastrointest Canc 30, 105–111 (2001). https://doi.org/10.1385/IJGC:30:3:105

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