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Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer

  • Epidemiology
  • Published:
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Abstract

Background An accumulating body of evidence suggests that there is an inverse relationship between the intake of folate (a water-soluble B-vitamin) and the risk of developing breast cancer. Individual variation in the genes involved in the transport of folate, or its metabolism, may affect risk, or may modify the association between folate and breast cancer risk. Methods We performed a case-control study to evaluate the association between common polymorphisms in six folate-related genes and the risk of breast cancer in 1,009 breast cancer patients and 907 healthy controls. Study subjects were genotyped for eight single nucleotide polymorphisms (SNPs) in these six genes. Results We observed no association between the MTHFR, RFC, MS and MTRR genotypes and the risk of breast cancer. Conclusion These data do not support the hypothesis that genetic variation in genes involved in the metabolism of folate are implicated in the etiology of breast cancer.

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References

  1. Kim YI (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10(2):66–88

    Article  PubMed  CAS  Google Scholar 

  2. Wagner C (1995) Biochemical role of folate in cellular metabolism. In: Bailey LB (ed) Folate in health and disease. Marcel Dekker Inc, New York, pp 23–42

    Google Scholar 

  3. Selhub J, Miller JW (1992) The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr 55(1):131–138

    PubMed  CAS  Google Scholar 

  4. Baylin SB et al (1998) Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 72:141–196

    Article  PubMed  CAS  Google Scholar 

  5. Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21(2):163–167

    Article  PubMed  CAS  Google Scholar 

  6. Duthie SJ (1999) Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull 55(3):578–592

    Article  PubMed  CAS  Google Scholar 

  7. Kim YI (2004) Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studies. Environ Mol Mutagen 44(1):10–25

    Article  PubMed  CAS  Google Scholar 

  8. Zhang SM (2004) Role of vitamins in the risk, prevention, and treatment of breast cancer. Curr Opin Obstet Gynecol 16(1):19–25

    Article  PubMed  CAS  Google Scholar 

  9. Eichholzer M et al (2001) Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence. Swiss Med Wkly 131(37–38):539–549

    PubMed  CAS  Google Scholar 

  10. Lewis SJ et al (2006) Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk. J Natl Cancer Inst 98(22):1607–1622

    Article  PubMed  CAS  Google Scholar 

  11. Zhang S et al (1999) A prospective study of folate intake and the risk of breast cancer. Jama 281(17):1632–1637

    Article  PubMed  CAS  Google Scholar 

  12. Rohan TE et al (2000) Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 92(3):266–269

    Article  PubMed  CAS  Google Scholar 

  13. Sellers TA et al (2001) Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 12(4):420–428

    Article  PubMed  CAS  Google Scholar 

  14. Shrubsole MJ et al (2001) Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res 61(19):7136–7141

    PubMed  CAS  Google Scholar 

  15. Sharp L, Little J (2004) Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol 159(5):423–443

    Article  PubMed  Google Scholar 

  16. Ulrich CM, Robien K, Sparks R (2002) Pharmacogenetics and folate metabolism – a promising direction. Pharmacogenomics 3(3):299–313

    Article  PubMed  CAS  Google Scholar 

  17. Justenhoven C et al (2005) One-carbon metabolism and breast cancer risk: no association of MTHFR, MTR, and TYMS polymorphisms in the GENICA study from Germany. Cancer Epidemiol Biomarkers Prev 14(12):3015–3018

    Article  PubMed  CAS  Google Scholar 

  18. Zhai X et al (2006) Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis. BMC Cancer 6:138

    Article  PubMed  CAS  Google Scholar 

  19. Xu WH et al (2007) Dietary folate intake, MTHFR genetic polymorphisms, and the risk of endometrial cancer among Chinese women. Cancer Epidemiol Biomarkers Prev 16(2):281–287

    Article  PubMed  CAS  Google Scholar 

  20. Zintzaras E (2006) Methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a meta-analysis. Clin Genet 69(4):327–336

    Article  PubMed  CAS  Google Scholar 

  21. Mason JB, Rosenberg IH (1994) Intestinal absorption of folate. In: Johnson LR (ed) Physiology of the gastrointestinal tract. Raven, New York

    Google Scholar 

  22. Shane B (1995) Folate chemistry and metabolism. In: Bailey LB (ed) Folate in health and disease. Marcel Dekker Inc, New York, pp 1–22

    Google Scholar 

  23. Chango A et al (2000) A polymorphism (80G→A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab 70(4):310–315

    Article  PubMed  CAS  Google Scholar 

  24. Schirch L, Peterson D (1980) Purification and properties of mitochondrial serine hydroxymethyltransferase. J Biol Chem 255(16):7801–7806

    PubMed  CAS  Google Scholar 

  25. Schirch L (1982) Serine hydroxymethyltransferase. Adv Enzymol Relat Areas Mol Biol 53:83–112

    Article  PubMed  CAS  Google Scholar 

  26. Heil SG et al (2001) Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Mol Genet Metab 73(2):164–172

    Article  PubMed  CAS  Google Scholar 

  27. Frosst P et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113

    Article  PubMed  CAS  Google Scholar 

  28. Weisberg I et al (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64(3):169–172

    Article  PubMed  CAS  Google Scholar 

  29. Sharp L et al (2002) Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett 181(1):65–71

    Article  PubMed  CAS  Google Scholar 

  30. Le Marchand L et al (2004) MTHFR polymorphisms, diet, HRT, and breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 13(12):2071–2077

    PubMed  CAS  Google Scholar 

  31. Campbell IG et al (2002) Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer. Breast Cancer Res 4(6):R14

    Article  PubMed  Google Scholar 

  32. Gershoni-Baruch R et al (2000) Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women. Eur J Cancer 36(18):2313–2316

    Article  PubMed  CAS  Google Scholar 

  33. Rady PL et al (2002) Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A. Am J Med Genet 107(2):162–168

    Article  PubMed  Google Scholar 

  34. Leclerc D et al (1996) Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Hum Mol Genet 5(12):1867–1874

    Article  PubMed  CAS  Google Scholar 

  35. Harmon DL et al (1999) Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. Genet Epidemiol 17(4):298–309

    Article  PubMed  CAS  Google Scholar 

  36. Pufulete M et al (2005) Influence of folate status on genomic DNA methylation in colonic mucosa of subjects without colorectal adenoma or cancer. Br J Cancer 92(5):838–842

    Article  PubMed  CAS  Google Scholar 

  37. Wilson A et al (1999) A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab 67(4):317–323

    Article  PubMed  CAS  Google Scholar 

  38. Gaughan DJ et al (2001) The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis 157(2):451–456

    Article  PubMed  CAS  Google Scholar 

  39. Geisel J et al (2001) Genetic defects as important factors for moderate hyperhomocysteinemia. Clin Chem Lab Med 39(8):698–704

    Article  PubMed  CAS  Google Scholar 

  40. O’Leary VB et al (2002) MTRR and MTHFR polymorphism: link to Down syndrome? Am J Med Genet 107(2):151–155

    Article  PubMed  Google Scholar 

  41. Kraus JP et al (1998) The human cystathionine beta-synthase (CBS) gene: complete sequence, alternative splicing, and polymorphisms. Genomics 52(3):312–324

    Article  PubMed  CAS  Google Scholar 

  42. Shen M et al (2005) Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China. Lung Cancer 49(3):299–309

    Article  PubMed  Google Scholar 

  43. Shrubsole MJ et al (2004) MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev 13(2):190–196

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Joanne Kotsopoulos is supported by a fellowship from the Canadian Breast Cancer Foundation, Ontario Chapter.

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Authors and Affiliations

  1. Women’s College Research Institute, Women’s College Hospital, University of Toronto, 790 Bay Street, 7th Floor, Room 750, Toronto, Canada, M5G 1N8

    Joanne Kotsopoulos, William W. Zhang, Shiyu Zhang, Phil Zhang, Ping Sun & Steven A. Narod

  2. Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada

    Joanne Kotsopoulos

  3. Surgical Oncology, University Health Network, Toronto, ON, Canada

    David McCready

  4. Medical Oncology and Hematology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Maureen Trudeau

Authors
  1. Joanne Kotsopoulos
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  2. William W. Zhang
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  3. Shiyu Zhang
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  4. David McCready
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  5. Maureen Trudeau
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  6. Phil Zhang
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  7. Ping Sun
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  8. Steven A. Narod
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Correspondence to Steven A. Narod.

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Kotsopoulos, J., Zhang, W.W., Zhang, S. et al. Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer. Breast Cancer Res Treat 112, 585–593 (2008). https://doi.org/10.1007/s10549-008-9895-6

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  • DOI: https://doi.org/10.1007/s10549-008-9895-6

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