Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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Interactions Between MTHFR C677T - A1298C Variants and Folic Acid Deficiency Affect Breast Cancer Risk in a Chinese Population

  • Wu, Xia-Yu (School of Life Sciences, Yunnan University) ;
  • Ni, Juan (School of Life Sciences, The Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, Yunnan Normal University) ;
  • Xu, Wei-Jiang (School of Life Sciences, The Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, Yunnan Normal University) ;
  • Zhou, Tao (School of Life Sciences, The Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, Yunnan Normal University) ;
  • Wang, Xu (School of Life Sciences, Yunnan University)
  • Published : 2012.05.30
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Abstract

Background: Our objective was to evaluate the MTHFR C677T-A1298C polymorphisms in patients with breast cancer and in individuals with no history of cancer, to compare the levels of genetic damage and apoptosis under folic acid (FA) deficiency between patients and controls, and to assess associations with breast cancer. Methods: Genetic damage was marked by micronucleated binucleated cells (MNBN) and apoptosis was estimated by cytokinesis-block micronucleus assay (CBMN). PCR-RFLP molecular analysis was carried out. Results: The results showed significant associations between the MTHFR 677TT or the combined MTHFR C677T-A1298C and breast cancer risk (OR = 2.51, CI = 0.85 to 7.37, p = 0.08; OR = 4.11, CI = 0.78 to 21.8, p < 0.001). The MNBN from the combined MTHFR C677T-A1298C was higher and the apoptosis was lower than that of the single variants (p < 0.05). At 15 to 60 nmol/L FA, the MNBN in cases with the TTAC genotype was higher than controls (p < 0.05), whereas no significant difference in apoptosis was found between the cases and controls after excluding the genetic background. Conclusions: Associations between the combined MTHFR C677T-A1298C polymorphism and breast cancer are possible from this study. A dose of 120 nmol/L FA could enhance apoptosis in cases with MTHFR C677T-A1298C. Breast cancer individuals with the TTAC genotype may be more sensitive to the genotoxic effects of FA deficiency than controls.

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References

  1. Andrew JV, Douglas GA (2001). Analysing controlled trials with baseline and follow up measurements. Brit Med J, 323, 1123-4. https://doi.org/10.1136/bmj.323.7321.1123
  2. Beilbya J, Ingramb D, Hahnelc R, Rossia E (2004). Reduced breast cancer risk with increasing serum folate in a case-control study of the C677T genotype of the methylenetetrahydrofolate reductase gene. Eur J Cancer, 40, 1250-4. https://doi.org/10.1016/j.ejca.2004.01.026
  3. Bistulfi G, Vandette E, Matsui S, Smiraglia DJ (2010). Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells. BMC Biol, 8, 6. https://doi.org/10.1186/1741-7007-8-6
  4. Bouckaert KP, Slimani N, Nicolas G, et al (2011). Critical evaluation of folate data in European and international databases: Recommendations for standardization in international nutritional studies. Mol Nutr Food Res, 55, 166-80. https://doi.org/10.1002/mnfr.201000391
  5. Campbell IG, Baxter SW, Eccles DM, Choong DY (2002). Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer. Breast Cancer Res, 4, R14. https://doi.org/10.1186/bcr457
  6. Celtikci B, Lawrance AK, Wu Q, Rozen R (2009). Methotrexateinduced apoptosis is enhanced by altered expression of methylenetetrahydrofolate reductase. Anticancer Drugs, 20, 787-93. https://doi.org/10.1097/CAD.0b013e32832f4aa8
  7. Crott JW, Mashiyama ST, Ames BN, Fenech M (2001). The effect of folic acid deficiency and MTHFR C677T polymorphism on chromosome damage in human lymphocytes in vitro. Cancer Epidemiol Biomarkers Prev, 10, 1089-96.
  8. Dhillon V, Thomas P, Fenech M (2009). Effect of common polymorphisms in folate uptake and metabolism genes on frequency of micronucleated lymphocytes in a South Australian cohort. Mutat Res, 665, 1-6. https://doi.org/10.1016/j.mrfmmm.2009.02.007
  9. Eichholzer M, Tonz O, Zimmermann R (2006). Folic acid: a public-health challenge. Lancet, 367, 1352-61. https://doi.org/10.1016/S0140-6736(06)68582-6
  10. Everson RB, Wehr CM, Erexson GL, MacGregor JT (1988). Association of marginal folate depletion with increased human chromosomal damage in vivo: demonstration by analysis of micronucleated erythrocytes. J Natl Cancer Inst, 80, 525-9. https://doi.org/10.1093/jnci/80.7.525
  11. Fenech M, Crott JW (2002). Micronuclei, nucleoplasmic bridges and nuclear buds induced in folic acid deficient human lymphocytes-evidence for breakage- fusion-bridge cycles in the cytokinesis-block micronucleus assay. Mutat Res, 504, 131-6. https://doi.org/10.1016/S0027-5107(02)00086-6
  12. Fenech M (2006). Cytokinesis-block micronucleus assay evolves into a "cytome" assay of chromosomal instability, mitotic dysfunction and cell death. Mutat Res, 600, 58-66. https://doi.org/10.1016/j.mrfmmm.2006.05.028
  13. Fenech M (2001). The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res, 475, 56-67.
  14. Friso S, Choi SW, Girelli D, et al (2002). A common mutation in the 5, 10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate staus. Proc Natl Acad Sci USA, 99, 5606-11. https://doi.org/10.1073/pnas.062066299
  15. Guttenbach M, Schmid M (1994). Exclusion of specific human chromosomes into micronuclei by 5-azacytidine treatment in lymphocyte cultures. Exp Cell Res, 211, 127-32. https://doi.org/10.1006/excr.1994.1068
  16. Huang L, Song X, Zhu W, Li Y (2008). Plasma homocysteine and gene polymorphisms associated with the risk of hyperlipidemia in northern Chinese subjects. Biomed Environ Sci, 21, 514-20. https://doi.org/10.1016/S0895-3988(09)60011-8
  17. Johnson J, Mejia de EG (2011). Dietary factors and pancreatic cancer. The role of food bioactive compounds. Mol Nutr Food Res, 55, 58-73. https://doi.org/10.1002/mnfr.201000420
  18. Kim YI (1999). Folate and carcinogenesis: evidence, mechanisms and implications. J Nutr Biochem, 10, 66-8. https://doi.org/10.1016/S0955-2863(98)00074-6
  19. Kim YI, Baik HW, Fawaz K, et al (2001). Effects of folate supplementation on two provisional molecular markers of colon cancer: a prospective, randomized trial. Am J Gastroenterol, 96, 184-95. https://doi.org/10.1111/j.1572-0241.2001.03474.x
  20. Lin KW, Birmingham E (2010). Folic Acid for the prevention of neural tube defects. Am Fam Physician, 82, 1533.
  21. Maruti SS, Ulrich CM, White E (2009). Folate and one-carbon metabolism nutrients from supplements and diet in relation to breast cancer risk. Am J Clin Nutr, 89, 624-33. https://doi.org/10.3945/ajcn.2008.26568
  22. Mazza D, Chapman A (2010). Improving the uptake of preconception care and periconceptional folate supplementation: what do women think. BMC Public Health, 23, 786.
  23. Ni J, Lu L, Fenech M, Wang X (2010). Folate Deficiency in Human peripheral blood lymphocytes induces chromosome 8 aneuploidy but this effect is not modified by riboflavin. Environ Mol Mutagen, 51, 15-22.
  24. Promthet SS, Pientong C, Ekalaksananan T, et al (2010). Risk factors for colon cancer in Northeastern Thailand: interaction of MTHFR codon 677 and 1298 genotypes with environmental factors. J Epidemiol, 20, 329-338. https://doi.org/10.2188/jea.JE20090140
  25. Quinlivan EP, Davis SR, Shelnutt KP, et al (2005). Methylenetetrahydrofolate reductase 677Cg $\rightarrow$ T polymorphism and folate status affect one-carbon incorporation into human DNA deoxynucleosides. J Nutr, 135, 389-96. https://doi.org/10.1093/jn/135.3.389
  26. Rampersaud GC, Kauwell GP, Hutson AD, Cerda JJ, Bailey LB (2000). Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. Am J Clin Nutr, 72, 998-1003. https://doi.org/10.1093/ajcn/72.4.998
  27. Rodrigues JO, Galbiatti AL, Ruiz MT (2010). Polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene and risk of head and neck squamous cell carcinoma. Braz J Otorhinolaryngol, 76, 776-82. https://doi.org/10.1590/S1808-86942010000600017
  28. Ruosaari ST, Nymark PE, Aavikko MM, et al (2008). Aberrations of chromosome 19 in asbestos-associated lung cancer and in asbestos-induced micronuclei of bronchial epithelial cells in vitro. Carcinogenesis, 29, 913-17. https://doi.org/10.1093/carcin/bgn068
  29. Skibola CF, Smith MT, Hubbard A, et al (1999). Polymorphism in the methylene-tetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA, 96, 12810-5. https://doi.org/10.1073/pnas.96.22.12810
  30. Song J, Geltinger C, Sun K, Kanazawa I, Yokoyama KK (1999). Direct lysis method for the rapid preparation of plasmid DNA. Anal Biochem, 271, 89-91. https://doi.org/10.1006/abio.1999.4106
  31. Suleeporn S, Yasunori S, Hiromi S, et al (2010). Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case-control study in Thai women. Breast Cancer Res Treat, 123, 885-93. https://doi.org/10.1007/s10549-010-0804-4
  32. Thomas P, Fenech M (2008). Chromosome 17 and 21 aneuploidy in buccal cells is increased with ageing and in Alzheimer's disease. Mutagenesis, 23, 57-65.
  33. Thomas P, Fenech M (2008). Methylenetetrahydrofolate reductase, common polymorphisms, and relation to disease. Vitam Horm, 79, 375-92. https://doi.org/10.1016/S0083-6729(08)00413-5
  34. Wang X, Thomas P, Xue J, Fenech M (2004). Folate deficiency induces aneuploidy in human lymphocytes in vitro-evidence using cytokinesis-blocked cells and probes specific for chromosomes 17 and 21. Mutation Res, 551, 167-80. https://doi.org/10.1016/j.mrfmmm.2004.03.008
  35. Wang X, Wu X, Liang Z, et al (2006). A comparison of folic acid deficiency-induced genomic instability in lymphocytes of breast cancer patients and normal non-cancer controls from a Chinese population in Yunnan. Mutagenesis, 21, 41-7. https://doi.org/10.1093/mutage/gei069
  36. Wei Q, Shen H, Wang LE, et al (2003). Association between low dietary folate intake and suboptimal cellular DNA repair capacity. Cancer Epidemiol Biomarkers Prev, 12, 963-9.
  37. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998). A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab, 64, 169-72. https://doi.org/10.1006/mgme.1998.2714
  38. Wu X, Liang Z, Zou T, Wang X (2009). Effects of folic acid deficiency and MTHFR C677T polymorphisms cytotoxicity in human peripheral blood lymphocytes. BBRC, 379, 732-7.
  39. Xiao WL, Wu M, Shi B (2006). Folic acid rivals methylenetetrahydrofolate reductase (MTHFR) genesilencing effect on MEPM cell proliferation and apoptosis. Mol Cell Biochem, 292, 145-54. https://doi.org/10.1007/s11010-006-9228-1
  40. Xu GL, Bestor TH, Bourc'his D, et al (1999). Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature, 402, 187-91. https://doi.org/10.1038/46052
  41. Yang QH, Botto LD, Gallagher M, et al (2008). Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank. Am J Clin Nutr, 88, 232-46. https://doi.org/10.1093/ajcn/88.1.232
  42. Yi P, Pogribny I, James JS (2002). Multiplex PCR for simultaneous detection of 677Cg$\rightarrow$ T and 1298Ag$\rightarrow$ C polymorphisms in methylenetetrahydrofolate reductase gene for population studies of cancer risk. Cancer Lett, 181, 209-13. https://doi.org/10.1016/S0304-3835(02)00060-5
  43. Zoodsma M, Nolte IM, Schipper M, et al (2005). Methylenetetrahydrofolate reductase (MTHFR) and susceptibility for (pre)neoplastic cervical disease. Hum Genet, 116, 247-54. https://doi.org/10.1007/s00439-004-1233-4

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