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Polymorphisms in methylenetetrahydrofolate reductase gene (MTHFR) and the age of onset of sporadic colorectal adenocarcinoma

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Abstract

Background and aims

Evidence is accumulating for a role of folate in the aetiology of colorectal cancer (CRC). The methylenetetrahydrofolate reductase (MTHFR) gene, involved in folate metabolism, is polymorphic in humans. Since it is unknown whether the MTHFR C677T and A1298C polymorphisms alter the risk for CRC, this was the aim of our study.

Materials and methods

Genomic DNA from 102 sporadic colorectal adenocarcinoma (SCA) patients and 300 controls was analyzed by polymerase chain reaction followed by restriction digestion for the polymorphisms analyses.

Results/findings

The frequencies of MTHFR C677T and A1298C genotypes were similar in patients and controls. Similar overall risks for disease were seen in individuals with the distinct MTHFR genotypes. However, an excess of the MTHFR 677TT and 677CT genotypes was seen in patients under 50 years, compared with patients at an older age (19.2 vs 13.1% and 61.6 vs 39.5%, respectively; P = 0.04). The differences were more prominent when the frequency of the 677TT plus 677CT genotype was seen in both group of patients (80.8 vs 52.6%, respectively; P = 0.01), and in younger patients compared to controls (80.8 vs 52.3%, P < 0.01). Individuals with the combined genotype had 3.82-fold (95% confidence interval, 1.41–10.42) increased risk of developing SCA under 50 years, compared with those harboring the wild-type genotype.

Interpretation/conclusion

These results suggest a role for the MTHFR 677TT plus 677CT genotype in increasing SCA diagnosed at a low age in southeastern Brazil, but additional studies with larger sample sizes should be carried out to clarify this issue.

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References

  1. Kim Y-I (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10:66–88

    Article  PubMed  CAS  Google Scholar 

  2. Little J, Sharp L (2002) Colorectal neoplasia and genetic polymorphisms associated with folate metabolism. Eur J Cancer Prev 11:105–110

    Article  PubMed  CAS  Google Scholar 

  3. Pufulete M, Al-Ghnaniem R, Leather AJM, Appleby P, Gout S, Terry C, Emery PW, Sanders TAB (2003) Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 124:1240–1248

    Article  PubMed  CAS  Google Scholar 

  4. Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21:163–167

    Article  PubMed  CAS  Google Scholar 

  5. Eichholzer M, Lüthy F, Moser U, Fowler B (2001) Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence. Swiss Med Wkly 131:539–549

    PubMed  CAS  Google Scholar 

  6. Van Der Put NMJ, Gabreels F, Stevens EM, Smeitink JÁ, Trijbels FJ, Eskes TK, Van Den Heuvel LP, Blom HJ (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk for neural-tube defects? Am J Hum Genet 62:1044–1051

    Article  PubMed  Google Scholar 

  7. Johnson WG (1999) DNA polymorphism-diet-cofactor-development hypothesis and the gene–teratogen model for schizophrenia and other developmental disorders. Am J Med Genet 88:311–323

    Article  PubMed  CAS  Google Scholar 

  8. Slaterry Ml, Poter JD, Samowitz W, Shaffer D, Leppert M (1999) Methylenetetrahydrofolate reductase, diet and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 8:513–518

    Google Scholar 

  9. Ma J, Stampfer MJ, Artigas C, Hunter DJ, Fuchs C, Willet WC, Selhub J, Hennekens CH, Rozen R (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 57:1098–1102

    PubMed  CAS  Google Scholar 

  10. Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, Conley MR, Weir DG, Scott JM (1997) Thermolable variant of 5,10-methylene-tetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 349:1591–1593

    Article  PubMed  CAS  Google Scholar 

  11. Friedman G, Goldschmidt N, Friedlander Y, Bem-Yehuda A, Selhub J, Babaey S, Mendel M, Kidron M, Bar-On H (1999) A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr 129:1656–1661

    PubMed  CAS  Google Scholar 

  12. Chen J, Ma J, Stampfer MJ, Palomeque C, Selhub J, Hunter DJ (2002) Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contribution to risk of colorectal cancer. Pharmacogenetics 12:339–342

    Article  PubMed  CAS  Google Scholar 

  13. Chen J, Giovannucci E, Kelsey K, Rimm EB, Stampfer MJ, Colditz GA, Spiegelman D, Willet WC, Hunter DJ (1996) A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 56:4862–4864

    PubMed  CAS  Google Scholar 

  14. Chen J, Giovannucci EL, Hunter DJ (1999) MTHFR polymorphism, methyl-replete diets and the risk of colorectal carcinoma and adenoma among U.S. men and women: an example of gene–environmental interactions in colorectal tumorigenesis. J Nutr 129:560S–564S

    PubMed  CAS  Google Scholar 

  15. Park KS, Mok JW, Kim JC (1999) The 677C>T mutation in 5,10-methylene-tetrahydrofolate reductase and colorectal cancer risk. Genet Test 3:233–236

    PubMed  CAS  Google Scholar 

  16. Delgado-Enciso I, Martinez-Garza SG, Rojas-Martinez A, Ortiz-Lopez R, Bosques-Padilla F, Calderon-Garciduenas AL, Zarate-Gomez M, Barrera-Saldana HÁ (2001) 677T mutation of the MTHFR gene in adenomas and colorectal cancer in a population sample from the northeastern Mexico (in Spanish). Rev Gastroenterol Mex 66:32–37

    PubMed  CAS  Google Scholar 

  17. Keku T, Millikan R, Worley K, Winckel S, Eaton A, Martin C, Sandler R (2002) 5,10-methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites. Cancer Epidemiol Biomarkers Prev 11:1611–1621

    PubMed  CAS  Google Scholar 

  18. Le Marchand L, Donlon T, Hankin JH, Kolonel LN, Wilkens LR, Seifried A (2002) B-vitamin intake, metabolic genes, and colorectal cancer risk (United States). Cancer Causes Control 13:239–248

    Article  PubMed  Google Scholar 

  19. Shannon B, Gnanasampanthan S, Beilby J, Lacopetta B (2002) A polymorphism in the methylenetetrahydrofolate reductase gene predisposes to colorectal cancers with microsatellite instability. Gut 50:520–524

    Article  PubMed  CAS  Google Scholar 

  20. Sharp L, Little J, Brockton N (2002) Dietary intake of folate and related micronutrients, genetic polymorphisms in MTHFR and colorectal cancer: a population-based case control study in Scotland (Abstract). J Nutr 132:3542S

    Google Scholar 

  21. Toffoli G, Gafa R, Russo A, Lanza G, Dolcetti R, Sartor F, Libra M, Viel A, Boiocchi M (2003) Methylenetetrahydrofolate reductase 677C>T polymorphism and risk of proximal cancer in north Italy. Clin Cancer Res 9:743–748

    PubMed  CAS  Google Scholar 

  22. Arruda VR, Grignolli CE, Gonçalves MS, Soares MC, Menezes R, Saad STO, Costa FF (1998) Prevalence of homozygosity for the deleted alleles of glutathione S-transferase mu (GSTM1) and theta (GSTT1) among distinct ethnic groups from Brazil: relevance to environmental carcinogenesis? Clin Genet 54:210–214

    PubMed  CAS  Google Scholar 

  23. Alves-Silva J, Da Silva-Santos M, Guimaraes PE, Ferreira AC, Bandelt HJ, Pena SD, Prado VF (2000) The ancestry of Brazilian mtDNA lineages. Am J Hum Genet 67:444–461

    Article  PubMed  CAS  Google Scholar 

  24. Carvalho-Silva DR, Santos FR, Rocha J, Pena SD (2001) The phylogeography of Brazilian Y-chromosome lineages. Am J Hum Genet 68:281–286

    Article  PubMed  CAS  Google Scholar 

  25. Duncan BB, Schmidt MI, Polanczyk CA, Mengue SS (1992) High mortality rates among Brazilian adult populations: an international comparison. Rev Assoc Med Bras 38:138–144

    PubMed  CAS  Google Scholar 

  26. Mattos LL, Martins IS (2000) Dietary fiber consumption in an adult population. Rev Saude Publica 34:50–55

    Article  PubMed  CAS  Google Scholar 

  27. Freedman NA, Michalek AM, Marshall JR, Mettlin CJ, Petrelli NJ, Zhang Z-F, Black JD, Satchidanand S, Asirwatham JE (1996) The relationship between smoking exposure and p53 overexpression in colorectal cancer. Br J Cancer 73:902–908

    PubMed  CAS  Google Scholar 

  28. Broders AC (1925) The grading of carcinoma. Minn Med 8:726–730

    Google Scholar 

  29. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DJ, Morrow M (2002) Colon and rectum. In: Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DJ, Morrow M (eds) American joint committee on cancer-cancer staging manual. Springer, Berlin Heidelberg New York, pp 113–123

    Google Scholar 

  30. Astler VB, Coller FA (1954) The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann Surg 139:846–851

    Article  PubMed  CAS  Google Scholar 

  31. Fosster P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, Den Heijer M, Kluijtmans LA, Van Den Heuvel LP (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylene-tetrahydrofolate reductase. Nat Genet 10:111–113

    Article  Google Scholar 

  32. Ioannidis JP, Ntazani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309

    Article  PubMed  CAS  Google Scholar 

  33. De Jong MM, Noite IM, Meerman GJ, Van Der Graaf WTA, Vries EGE, Sijmons RH, Hofstra RMW, Kleibeuker JH (2002) Low-penetrance genes and their involvement in colorectal cancer susceptibility. Cancer Epidemiol Biomarkers Prev 11:1332–1352

    PubMed  Google Scholar 

  34. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN (2003) Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33:177–182

    Article  PubMed  CAS  Google Scholar 

  35. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG, MTHFR Studies Collaboration Group (2002) MTHFR 677C→T polymorphism and risk of coronary heart disease. JAMA 288:2023–2031

    Article  PubMed  CAS  Google Scholar 

  36. Chen K, Jiang QT, He HQ (2005) Relationship between metabolic enzyme polymorphism and colorectal cancer. World J Gastroenterol 11:331–335

    PubMed  CAS  Google Scholar 

  37. Sharp L, Little J (2004) Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a huge review. Am J Epidemiol 159:423–443

    Article  PubMed  Google Scholar 

  38. Bailey LB (2003) Folate, methyl-related nutrients, alcohol, and the MTHFR 677C>T polymorphism affect cancer risk: intake recommendations. J Nutr 133:3748S–3753S

    PubMed  CAS  Google Scholar 

  39. Kim Y (1997) Folate deficiency in rats induces DNA strand breaks and hypomethylation with the p53 tumor suppressor gene. Am J Clin Nutr 65:46–52

    PubMed  CAS  Google Scholar 

  40. Duthie SJ (1999) Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull 55:578–592

    Article  PubMed  CAS  Google Scholar 

  41. Kim Y, Giuliano AR, Hatch KD, Schneider A, Nour MA, Dallal GE (1994) Global DNA hypomethylation increases progressively in cervical dysplasia and carcinoma. Cancer 74:893–898

    Article  PubMed  CAS  Google Scholar 

  42. Fowler BM, Giuliano AR, Piyathilake C, Nour M, Hatch K (1998) Hypomethylation in cervical tissue: is there a correlation with folate status? Cancer Epidemiol Biomarkers Prev 7:901–906

    PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Mr. Roberto Zulli for checking the statistical analysis and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for the financial support.

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Authors and Affiliations

  1. Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, CP: 6111, 13083-970, Brazil

    Carmen S. P. Lima, Helvia Nascimento, Maria T. Teori & Fernando F. Costa

  2. Department of Genetics, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, CP: 6111, 13083-970, Brazil

    Luciana C. Bonadia & Carmen S. Bertuzzo

  3. Department of Digestive Surgery, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, CP: 6111, 13083-970, Brazil

    Claudio S. R. Coy & Juvenal R. N. Góes

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  1. Carmen S. P. Lima
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Correspondence to Carmen S. P. Lima.

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Lima, C.S.P., Nascimento, H., Bonadia, L.C. et al. Polymorphisms in methylenetetrahydrofolate reductase gene (MTHFR) and the age of onset of sporadic colorectal adenocarcinoma. Int J Colorectal Dis 22, 757–763 (2007). https://doi.org/10.1007/s00384-006-0237-z

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  • DOI: https://doi.org/10.1007/s00384-006-0237-z

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