Document Type : Original Research


1 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

2 Department of Clinical Biochemistry, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran

3 Department of Clinical Biochemistry, Kermanshah University of Medical Sciences

4 Fertility and Infertility Research Center, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran

5 Medical Biology Research Center, Kermanshah University of Medical Sciences


Background & Objective: Breast cancer (BC) is known to be the most prevalent cancer among women. One-carbon metabolism (OCM) disturbance might play an important role in the etiology of BC. The present study aimed to investigate the thymidylate synthase (TYMS), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and methionine synthase reductase (MTRR) variants as good candidates for studying the role of genetic variants of folate metabolizing enzymes in the risk of BC.
Methods: The present case-control study consisted of 100 BC patients and 141 healthy females. The TYMS 2R/3R (rs34743033), MTR c.2756A>G (rs1805087), and MTRR c.66A>G (rs1801394) variants were detected by polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (RFLP), and a designed amplification-refractory mutation system (ARMS) method, respectively.
Results: The 3R allele of TYMS enhanced the risk of BC by 2.84-fold (p <0.001). In the presence of TYMS 3R/3R, compared to TYMS 2R/3R, there was a trend toward enhancing the risk of metastasis by 4.15-fold (95% CI: 0.96-17.85, p =0.055). The frequencies of MTR c.2756A>G and MTRR c.66A>G variants were not significantly different among patients and controls.
Conclusion: We observed that the TYMS 3R is a risk allele for susceptibility to BC and this allele tends to increase the BC metastasis.


Main Subjects

  1. Rahimi Z, Yari K, Rahimi, Z. Matrix Metalloproteinase-9 -1562T allele and its combination with MMP-2 -735 C allele are risk factors for breast cancer. Asian Pac J Cancer Prev. 2015; 16:1175-1179. [DOI:10.7314/APJCP.2015.16.3.1175] [PMID]
  2. Yari K, Rahimi Z, Moradi MR, Rahimi Z. The MMP-2 -735 C allele is a risk factor for susceptibility to breast cancer. Asian Pac J Cancer Prev. 2014; 15: 6199-6203. [DOI:10.7314/APJCP.2014.15.15.6199] [PMID]
  3. Rahimi Z, Kasraei R, Najafi F, et al. Cancer notification at a referral hospital of Kermanshah, Western Iran (2006-2009). Asian Pac J Cancer Prev. 2015; 16: 133-137. [DOI:10.7314/APJCP.2015.16.1.133] [PMID]
  4. Waseem M, Hussain S.R, Kumar S, et al. Association of MTHFR (C677T) gene polymorphism with breast cancer in north India. Biomarkers in Cancer. 2016; 8 111-117. [DOI:10.4137/BIC.S40446] [PMID] [PMCID]
  5. Yari K, Rahimi Z, Payandeh M, Rahimi Z. MMP-7 A-181G polymorphism in breast cancer patients from Western Iran. Breast Care (Basel). 2015; 10:398-402. [DOI:10.1159/000442231] [PMID] [PMCID]
  6. Chen J, Gammon M.D Chan W, et al. One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Res. 2005; 65:1606-1614. [DOI:10.1158/0008-5472.CAN-04-2630] [PMID]
  7. Naushad S.H.M, Pavani A, Rupasree Y, et al. Association of aberrations in one-carbon metabolism with molecular phenotype and grade of breast cancer. Mol Carcinog. 2012; 51: E32-41. [DOI:10.1002/mc.21830] [PMID]
  8. Abdulrahman G.O. Jr, Rahman G.A. Epidemiology of breast cancer in Europe and Africa. J Cancer Epidemiol. 2012; 2012: 915610. [DOI:10.1155/2012/915610] [PMID] [PMCID]
  9. Naushad SM, Divya C, Ramaiah MJ, Hussain T, Alrokayan SA, Kutala VK. Population-level diversity in the association of genetic polymorphisms of one-carbonmetabolism with breast cancer risk. J Community Genet. 2016; 7:279-290. [DOI:10.1007/s12687-016-0277-1] [PMID] [PMCID]
  10. Cheng CW, Yu JC, Huang CS, Shieh JC, Fu YP, Wang HW, Wu PE, Shen CY. Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan. Breast Cancer Res Treat. 2008;111(1):145-55. [DOI:10.1007/s10549-007-9754-x] [PMID]
  11. DeRoo LA, Bolick SC, Xu Z, Umbach DM, Shore D, Weinberg CR, Sandler DP, Taylor JA. Global DNA methylation and one-carbon metabolism gene polymorphisms and the risk of breast cancer in the Sister Study. Carcinogenesis. 2014;35(2):333-8. [DOI:10.1093/carcin/bgt342] [PMID] [PMCID]
  12. Rahimi Z, Ahmadian Z, Akramipour R, Vaisi-Raygani A, Rahimi Z, Parsian A. Thymidylate synthase and methionine synthase polymorphisms are not associated with susceptibility to childhood acute lymphoblastic leukemia in Kurdish population from Western Iran. Mol Biol Rep. 2012; 39:2195-200. [DOI:10.1007/s11033-011-0968-y] [PMID]
  13. Ozen F, Erdis E, Sik E, Silan F, Uludag A, Ozdemir O. Germ-line MTHFR C677T, FV H1299R and PAI-1 5G/4G variations in breast carcinoma. Asian Pac J Cancer Prev. 2013;14, 2903-2908. [DOI:10.7314/APJCP.2013.14.5.2903] [PMID]
  14. Akilzhanova A, Nurkina Z, Momynaliev K, et al. Genetic profile and determinants of homocysteine levels in Kazakhstan patients with breast cancer. Anticancer Res. 2013; 33:4049-4059.
  15. Mohammad N.S, Yedluri R., Addepalli P, Gottumukkala S.R, Digumarti R.R, Kutala V.K. Aberrations in one-carbon metabolism induce oxidative DNA damage in sporadic breast cancer. Mol Cell Biochem. 2011; 349:159-167. [DOI:10.1007/s11010-010-0670-8] [PMID]
  16. Hu S, Liu HC, Xi SM. Methionine Synthase Reductase A66G Polymorphism is not Associated with Breast Cancer Susceptibility-a Meta-analysis. Asian Pac J Cancer Prev. 2014;15(7):3267-71. [DOI:10.7314/APJCP.2014.15.7.3267] [PMID]
  17. López-Cortés A, Echeverría C, Oña-Cisneros F, Sánchez ME, Herrera C, Cabrera-Andrade A, Rosales F, Ortiz M, Paz-y-Miño C. Breast cancer risk associated with gene expression and genotype polymorphisms of the folate-metabolizing MTHFR gene: a case-control study in a high altitude Ecuadorian mestizo population. Tumor Biol. 2015;36(8):6451-61. [DOI:10.1007/s13277-015-3335-0] [PMID]
  18. Rahimi Z, Mozafari H, Shahriari-Ahmadi A, Alimogaddam K, Ghavamzadeh A, Aznab M, et al. Deep venous thrombosis and thrombophilic mutations in western Iran: association with factor V Leiden. Blood Coagul Fibrinolysis. 2010;21(5):385-8. [DOI:10.1097/MBC.0b013e328330e69a] [PMID]
  19. Huber S, McMaster KJ, Voelkerding KV. Analytical evaluation of primer engineered multiplex polymerase chain reaction-Restriction fragment length polymorphism for detection of factor V Leiden and prothrombin G20210A. J Mol Diagn. 2000;2(3):153-7. [DOI:10.1016/S1525-1578(10)60631-9]
  20. Nalejska E, Mączyńska E, Lewandowska MA. Prognostic and predictive biomarkers: tools in personalized oncology. Mol Diagn Ther. 2014;18(3):273-84. [DOI:10.1007/s40291-013-0077-9] [PMID] [PMCID]
  21. Quintero-Ramos A, Gutiérrez-Rubio S.A, Del Toro-Arreola A, et al. Association between polymorphisms in the thymidylate synthase gene and risk of breast cancer in a Mexican population. Genet Mol Res 2014; 13:8749-8756. [DOI:10.4238/2014.October.27.16] [PMID]
  22. Suzuki T, Matsuo K, Hirose K, Hiraki A, Kawase T, Watanabe M, Yamashita T, Iwata H, Tajima K. One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis. 2008;29(2):356-62. [DOI:10.1093/carcin/bgm295] [PMID]
  23. Zhai X, Gao J, Hu Z, Tang J, Qin J, Wang S, Wang X, Jin G, Liu J, Chen W, Chen F. Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis. BMC Cancer. 2006;6(1):138. [DOI:10.1186/1471-2407-6-138] [PMID] [PMCID]
  24. Mohammad NS, Yedluri R, Addepalli P, Gottumukkala SR, Digumarti RR, Kutala VK. Aberrations in one-carbon metabolism induce oxidative DNA damage in sporadic breast cancer. Mol Cell Biochem. 2011;349(1-2):159-67. [DOI:10.1007/s11010-010-0670-8] [PMID]
  25. Wang J, Wang B, Bi J, Di J. The association between two polymorphisms in the TYMS gene and breast cancer risk: a meta-analysis. Breast Cancer Res. 2011;128(1):203-9. [DOI:10.1007/s10549-010-1314-0] [PMID]
  26. Jiang-hua Q, De-chuang J, Zhen-duo L, Shu-de C, Zhenzhen L. Association of methylenetetrahydrofolate reductase and methionine synthase polymorphisms with breast cancer risk and interaction with folate, vitamin B 6, and vitamin B 12 intakes. Tumor Biol. 2014;35(12):11895-901. [DOI:10.1007/s13277-014-2456-1] [PMID]
  27. Yu L, Chen J. Association of MHTFR Ala222Val (rs1801133) polymorphism and breast cancer susceptibility: An update meta-analysis based on 51 research studies. Diagn Pathol. 2012;7(1):171. [DOI:10.1186/1746-1596-7-171] [PMID] [PMCID]
  28. Wu XY, Ni J, Xu WJ, Zhou T, Wang X. Interactions between MTHFR C677T-A1298C variants and folic acid deficiency affect breast cancer risk in a Chinese population. Asian Pac J Cancer Prev. 2012;13(5):2199-206. [DOI:10.7314/APJCP.2012.13.5.2199] [PMID]
  29. He JM, Pu YD, Wu YJ, Qin R, Zhang QJ, Sun YS, Zheng WW, Chen LP. Association between dietary intake of folate and MTHFR and MTR genotype with risk of breast cancer. Genet Mol Res. 2014;13(4):8925-31. [DOI:10.4238/2014.October.31.7] [PMID]
  30. Zhong S, Xu J, Li W, Chen Z, Ma T, Zhao J. Methionine synthase A2756G polymorphism and breast cancer risk: an up-to-date meta-analysis. Gene. 2013;527(2):510-5. [DOI:10.1016/j.gene.2013.06.054] [PMID]
  31. Xu X, Gammon MD, Zhang H, Wetmur JG, Rao M, Teitelbaum SL, Britton JA, Neugut AI, Santella RM, Chen J. Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study. Carcinogenesis. 2007;28(7):1504-9. [DOI:10.1093/carcin/bgm061] [PMID]
  32. Kotsopoulos J, Zhang WW, Zhang S, McCready D, Trudeau M, Zhang P, Sun P, Narod SA. Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer. Breast Cancer Res Treat. 2008;112(3):585-93. [DOI:10.1007/s10549-008-9895-6] [PMID]
  33. Lajin B, Sakur AA, Ghabreau L, Alachkar A. Association of polymorphisms in one-carbon metabolizing genes with breast cancer risk in Syrian women. Tumor Biol. 2012;33(4):1133-9. [DOI:10.1007/s13277-012-0354-y] [PMID]
  34. Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Jin F, Zheng W. MTR and MTRR polymorphisms, dietary intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2006 Mar 1;15(3):586-8. [DOI:10.1158/1055-9965.EPI-05-0576] [PMID]
  35. Luo WP, Li B, Lin FY, Yan B, Du YF, Mo XF, Wang L, Zhang CX. Joint effects of folate intake and one-carbon-metabolizing genetic polymorphisms on breast cancer risk: a case-control study in China. Sci Rep. 2016;6(1):1-1. [DOI:10.1038/srep29555] [PMID] [PMCID]