Tumor Biology

, Volume 36, Issue 5, pp 3757–3762 | Cite as

Polymorphisms in the MTHFR gene are associated with breast cancer risk and prognosis in a Chinese population

  • Qing Lu
  • Ke Jiang
  • Qiong Li
  • Ya-Jie Ji
  • Wei-Li Chen
  • Xiao-Hong Xue
Research Article


Breast cancer is the most common cancer affecting women in China and the world. Folate supplementation is proven to be effective in reducing the risk of breast cancer or improving its prognosis. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. This study aims to examine whether single nucleotide polymorphisms (SNP) in the MTHFR gene are associated with risk and survival of breast cancer and serum folate levels in healthy controls. We genotyped nine tagging SNPs in the MTHFR gene in a case–control study, including 560 breast cancer cases and 560 healthy controls in China. We found that TT genotype of rs1801133 had significant increased risk of breast cancer [adjusted odds ratio (OR) = 1.60, 95 % confidence interval (CI) 1.12–2.28] compared with CC genotype, and CC genotype of rs9651118 conferred significant reduced risk of breast cancer (adjusted OR = 0.65, 95 % CI 0.45–0.95) compared to TT genotype. Haplotype analysis also showed that MTHFR CACCAA and AGTCAC haplotypes (rs12121543-rs13306553-rs9651118-rs1801133-rs4846048-rs1801131) had significant reduced risk of breast cancer (adjusted OR = 0.70, 95 % CI 0.58–0.86; adjusted OR = 0.57, 95 % CI 0.40–0.80) compared with CATTAA haplotype. Besides, MTHFR rs9651118 CC genotype was significantly associated with survival in breast cancer cases (adjusted hazard ratio (HR) = 0.63, 95 % CI 0.40–0.99). But none of the SNPs in the MTHFR gene was associated with serum folate level in healthy controls. These findings suggest that variants in the MTHFR gene may influence the risk and prognosis of breast cancer.


Folate Tagging SNP Haplotype Biomarker Susceptibility Survival 



This study was supported by the third specialist construction Program of Shanghai Clinical Chinese Medicine (ZYSNXD-YL-YSZK009).

Conflicts of interest


Supplementary material

13277_2014_3016_MOESM1_ESM.docx (14 kb)
Supplementary Table 1 (DOCX 14 kb)


  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 09/10/2014
  2. 2.
    Shah R, Rosso K, Nathanson SD. Pathogenesis, prevention, diagnosis and treatment of breast cancer. World J Clin Oncol. 2014;5:283–98.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Brody JG, Rudel RA, Michels KB, Moysich KB, Bernstein L, Attfield KR, et al. Environmental pollutants, diet, physical activity, body size, and breast cancer: where do we stand in research to identify opportunities for prevention? Cancer. 2007;109:2627–34.CrossRefPubMedGoogle Scholar
  4. 4.
    Anothaisintawee T, Wiratkapun C, Lerdsitthichai P, Kasamesup V, Wongwaisayawan S, Srinakarin J, et al. Risk factors of breast cancer: a systematic review and meta-analysis. Asia Pac J Public Health. 2013;25:368–87.CrossRefPubMedGoogle Scholar
  5. 5.
    Rawal R, Bertelsen L, Olsen JH. Cancer incidence in first-degree relatives of a population-based set of cases of early-onset breast cancer. Eur J Cancer. 2006;42:3034–40.CrossRefPubMedGoogle Scholar
  6. 6.
    Sharif S, Moran A, Huson SM, Iddenden R, Shenton A, Howard E, et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet. 2007;44:481–4.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Das PM, Singal R. DNA methylation and cancer. J Clin Oncol. 2004;22:4632–42.CrossRefPubMedGoogle Scholar
  8. 8.
    Shahzad K, Hai A, Ahmed A, Kizilbash N, Alruwaili J. A structured-based model for the decreased activity of Ala222Val and Glu429Ala methylenetetrahydrofolate reductase (MTHFR) mutants. Bioinformation. 2013;9:929–36.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Izmirli M. A literature review of MTHFR (C677T and A1298C polymorphisms) and cancer risk. Mol Biol Rep. 2013;40:625–37.CrossRefPubMedGoogle Scholar
  10. 10.
    Shujuan Y, Jianxing Z, Xin-Yue C. Methylenetetrahydrofolate reductase genetic polymorphisms and esophageal squamous cell carcinoma susceptibility: a meta-analysis of case-control studies. Pak J Med Sci. 2013;29:693–8.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Yu L, Chen J. Association of MTHFR Ala222Val (rs1801133) polymorphism and breast cancer susceptibility: an update meta-analysis based on 51 research studies. Diagn Pathol. 2012;7:171.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Lin DY, Zeng D, Millikan R. Maximum likelihood estimation of haplotype effects and haplotype-environment interactions in association studies. Genet Epidemiol. 2005;29:299–312.CrossRefPubMedGoogle Scholar
  14. 14.
    Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014;533:11–20.CrossRefPubMedGoogle Scholar
  15. 15.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111–3.CrossRefPubMedGoogle Scholar
  16. 16.
    Gao CM, Tang JH, Cao HX, Ding JH, Wu JZ, Wang J, et al. MTHFR polymorphisms, dietary folate intake and breast cancer risk in Chinese women. J Hum Genet. 2009;4:414–8.CrossRefGoogle Scholar
  17. 17.
    Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hébert JR, et al. MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai breast cancer study. Cancer Epidemiol Biomarkers Prev. 2004;13:190–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Liang H, Yan Y, Li T, Li R, Li M, Li S, et al. Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk in Chinese population: a meta-analysis of 22 case-control studies. Tumour Biol. 2014;35:1695–701.CrossRefPubMedGoogle Scholar
  19. 19.
    Swartz MD, Peterson CB, Lupo PJ, Wu X, Forman MR, Spitz MR, et al. Investigating multiple candidate genes and nutrients in the folate metabolism pathway to detect genetic and nutritional risk factors for lung cancer. PLoS One. 2013;8:e53475.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chen Y, Ying D, Deng YC AHL, Wang HJ, Ma YQ, et al. Relationship between MTHFR gene polymorphisms and susceptibility of esophageal cancer of Han nationality in Xinjiang. J Toxicol. 2009;23:429–32.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Qing Lu
    • 1
  • Ke Jiang
    • 1
  • Qiong Li
    • 1
  • Ya-Jie Ji
    • 1
  • Wei-Li Chen
    • 1
  • Xiao-Hong Xue
    • 1
  1. 1.Department of Breast Surgery, Yueyang Hospital of Integrated Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina

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