Skip to main content

Advertisement

SpringerLink
Log in

Association of C677T (rs1081133) and A1298C (rs1801131) Methylenetetrahydrofolate Reductase Variants with Breast Cancer Susceptibility Among Asians: A Systematic Review and Meta-Analysis

  • Review Paper
  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

This systematic review and meta-analysis were conducted to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with breast cancer (BC) in Asians. Systematic searches were conducted in PubMed, EMBASE, Web of Science, and Scopus by May 2020. Inter-study heterogeneity was also assessed with a Q test, along with I2 statistics. Random-effects models were applied to pooled crude ORs with corresponding 95% CIs for the genetic models. A total of 1097 identified results, along with 36 qualified studies were included: for MTHFR C677T polymorphism, a total of 36 studies was comprised of 11,261 cases and 13,318 controls and for MTHFR A1298C polymorphism, a number of 19 studies contained 7424 cases and 8204 controls. Likewise, for C677T polymorphism, an increased risk of BC was seen for the allelic (OR 1.21, 95% CI 1.09–1.33, P < 0.01, I2 = 78.9%), dominant (OR 1.17, 95% CI 1.05–1.30, P < 0.01, I2 = 71.8%), recessive (OR 1.43, 95% CI 1.23–1.67, P < 0.01, I2 = 55.8%), and homozygous models (OR 1.48, 95% CI 1.25–1.75, P < 0.01, I2 59.9%) among BC patients compared to controls. Also, in terms of A1298C polymorphism, an association was found between the allelic (OR 1.15, 95% CI 1.04–1.28, P < 0.01, I2 70.4%) and homozygous models (OR 1.38, 95% CI 1.15–1.66, P < 0.01, I2 44.2%) with the risk of BC. In conclusion, findings revealed that MTHFR C677T variant might be a factor that predisposes BC in Asians. Furthermore, it was found that A1298C variant acts as a BC risk factor, particularly in a Western Asia population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Akilzhanova A et al (2013) Genetic profile and determinants of homocysteine levels in Kazakhstan patients with breast cancer. Anticancer Res 33:4049–4059

    CAS  PubMed  Google Scholar 

  • Akilzhanova A, Takamura N, Zhaojia Y, Aoyagi K, Karazhanova L, Yamashita S (2006) Kazakhstan: a folate-deficient area? Eur J Clin Nutr 60:1141–1143

    Article  CAS  PubMed  Google Scholar 

  • Akram M, Malik F, Kayani MA (2012) Mutational analysis of the MTHFR gene in breast cancer patients of Pakistani population. Asian Pac J Cancer Prev 13:1599–1603

    Article  PubMed  Google Scholar 

  • Antonaros F et al (2019) MTHFR C677T polymorphism analysis: a simple, effective restriction enzyme-based method improving previous protocols. Mol Genet Genom Med 7:e628

    Article  CAS  Google Scholar 

  • Botezatu A, Socolov D, Iancu IV, Huica I, Plesa A, Ungureanu C, Anton G (2013) Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and promoter methylation in cervical oncogenic lesions and cancer. J Cell Mol Med 17:543–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castiglia P et al (2019) Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in breast cancer: a Sardinian preliminary case-control study. Int J Med Sci 16:1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng H, Deng Z, Wang Z, Zhang W, Su J (2012) MTHFR C677T polymorphisms are associated with aberrant methylation of the IGF-2 gene in transitional cell carcinoma of the bladder. J Biomed Res 26:77–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi S-W, Mason JB (2000) Folate and carcinogenesis: an integrated scheme. J Nutr 130:129–132

    Article  CAS  PubMed  Google Scholar 

  • Chou Y-C et al (2006) Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case–control study in Taiwan. Carcinogenesis 27:2295–2300

    Article  CAS  PubMed  Google Scholar 

  • Del Gobbo GF, Price EM, Hanna CW, Robinson WP (2018) No evidence for association of MTHFR 677C> T and 1298A> C variants with placental DNA methylation. Clin Epigenet 10:34

    Article  CAS  Google Scholar 

  • Deligezer U, Akisik EE, Dalay N (2005) Homozygosity at the C677T of the MTHFR gene is associated with increased breast cancer risk in the Turkish population. In Vivo 19:889–893

    CAS  PubMed  Google Scholar 

  • Ergul E, Sazci A, Utkan Z, Canturk NZ (2003) Polymorphisms in the MTHFR gene are associated with breast cancer. Tumor Biol 24:286–290

    Article  CAS  Google Scholar 

  • Ferreira MA et al (2019) Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer. Nat Commun 10:1–18

    Article  CAS  Google Scholar 

  • Floris M et al (2020) MTHFR, XRCC1 and OGG1 genetic polymorphisms in breast cancer: a case-control study in a population from North Sardinia. BMC Cancer 20:1–15

    Article  CAS  Google Scholar 

  • Ghoncheh M, Mahdavifar N, Darvishi E, Salehiniya H (2016) Epidemiology, incidence and mortality of breast cancer in Asia Asian Pacific. J Cancer Prev 17:47–52

    Google Scholar 

  • He J et al (2014) Association between dietary intake of folate and MTHFR and MTR genotype with risk of breast cancer. Genet Mol Res 13:8925–8931

    Article  CAS  PubMed  Google Scholar 

  • He L, Shen Y (2017) MTHFR C677T polymorphism and breast, ovarian cancer risk: a meta-analysis of 19,260 patients and 26,364 controls. OncoTargets Ther 10:227–238. https://doi.org/10.2147/ott.s121472

    Article  CAS  Google Scholar 

  • Hedayatizadeh-Omran A, Alizadeh-Navaei R, Toghani-Hulari F, Amjadi O (2017) Association between MTHFR (C677T) gene polymorphism with breast cancer in Northern Iran. WCRJ 4:e876

    Google Scholar 

  • Hekim N, Ergen A, Yaylım İ, Yılmaz H, Zeybek Ü, Öztürk O, İsbir T (2007) No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer. Cell Biochem Funct 25:115–117

    Article  CAS  PubMed  Google Scholar 

  • Hesari A et al (2019) Evaluation of the two polymorphisms rs1801133 in MTHFR and rs10811661 in CDKN2A/B in breast cancer. J Cell Biochem 120:2090–2097

    Article  CAS  Google Scholar 

  • Hosseini M, Houshmand M, Ebrahimi A (2011) MTHFR polymorphisms and breast cancer risk. Arch Med Sci: AMS 7:134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang C-Y et al (2014) Evaluation of the contribution of methylenetetrahydrofolate reductase genotypes to Taiwan breast cancer. Anticancer Res 34:4109–4115

    CAS  PubMed  Google Scholar 

  • Jiang-hua Q, De-chuang J, Zhen-duo L, Shu-de C, Zhenzhen L (2014) 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 35:11895–11901

    Article  CAS  Google Scholar 

  • Kalyankumar C, Jamil K (2006) Methylene tetrahydofolate reductase (MTHFR) C677T and A1298C polymorphisms and breast cancer in South Indian population. Int J Cancer Res 2:143–151

    Article  CAS  Google Scholar 

  • Kaya EF, Karakus N, Ulusoy AN, Özaslan C, Kara N (2016) Association of the MTHFR gene C677T polymorphism with breast cancer in a Turkish population. Oncol Res Treat 39:534–538

    Article  CAS  PubMed  Google Scholar 

  • Kumar P, Yadav U, Rai V (2015) Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: evidence for genetic susceptibility. Meta Gene 6:72–84

    Article  PubMed  PubMed Central  Google Scholar 

  • Lajin B, Sakur AA, Ghabreau L, Alachkar A (2012) Association of polymorphisms in one-carbon metabolizing genes with breast cancer risk in Syrian women. Tumor Biol 33:1133–1139

    Article  CAS  Google Scholar 

  • Lee S-A et al (2004) Methylenetetrahydrofolate reductase polymorphism, diet, and breast cancer in Korean women. Exp Mol Med 36:116–121

    Article  CAS  PubMed  Google Scholar 

  • Lin W-Y et al (2004) The MTHFR C677T polymorphism, estrogen exposure and breast cancer risk: a nested case-control study in Taiwan. Anticancer Res 24:3863–3868

    CAS  PubMed  Google Scholar 

  • Liu Y, Zhou L-S, Xu X-M, Deng L-Q, Xiao Q-K (2013) Association of dietary intake of folate, vitamin B 6 and B 12 and MTHFR genotype with breast cancer risk Asian Pacific. J Cancer Prev 14:5189–5192

    Google Scholar 

  • Lu Q, Jiang K, Li Q, Ji Y-J, Chen W-L, Xue X-H (2015) Polymorphisms in the MTHFR gene are associated with breast cancer risk and prognosis in a Chinese population. Tumor Biol 36:3757–3762

    Article  CAS  Google Scholar 

  • Meneses-Sanchez P, Garcia-Hernandez SC, Porchia LM, Pérez-Fuentes R, Torres-Rasgado E, Soto ADA, Gonzalez-Mejia ME (2019) C677T and A1298C methylenetetrahydrofolate reductase polymorphisms and breast cancer susceptibility among Latinos: a meta-analysis. Breast Cancer 26:602–611

    Article  PubMed  Google Scholar 

  • Mir MM, Dar JA, Dar NA, Dar MS, Salam I, Lone MM, Chowdary NA (2008) Combined impact of polymorphism of folate metabolism genes; glutamate carboxypeptidase, methylene tetrahydrofolate reductase and methionine synthase reductase on breast cancer susceptibility in Kashmiri women. Int J Health Sci 2:3

    Google Scholar 

  • Mohammadzadeh G, Karimi M, Bazyar M, Hosseini S-M (2016) Lack of association between MTHFR C677T polymorphism and breast cancer risk in Ahvaz, west south-Iran. Adv Biomed Res. https://doi.org/10.4103/2277-9175.176352

    Article  PubMed  PubMed Central  Google Scholar 

  • Momenimovahed Z, Salehiniya H (2019) Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer: Targets Ther 11:151

    Google Scholar 

  • Mubarik S, Malik SS, Wang Z, Li C, Fawad M, Yu C (2019) Recent insights into breast cancer incidence trends among four Asian countries using age-period-cohort model. Cancer Manage Res 11:8145

    Article  Google Scholar 

  • Naushad SM, Pavani A, Digumarti RR, Gottumukkala SR, Kutala VK (2011) Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer. Mol Biol Rep 38:4893–4901

    Article  CAS  PubMed  Google Scholar 

  • Niu Z, Zhao H, Hou X (2017) Association of MTHFR, MTRR and MTR polymorphisms with breast cancer risk: a study in Chinese females. Int J Clin Exp Pathol 10:7059–7066

    Google Scholar 

  • Odin E, Wettergren Y, Carlsson G, Danenberg PV, Termini A, Willén R, Gustavsson B (2006) Expression and clinical significance of methylenetetrahydrofolate reductase in patients with colorectal cancer. Clin Colorectal Cancer 5:344–349

    Article  CAS  PubMed  Google Scholar 

  • Ozen F, Erdis E, Sik E, Silan F, Uludag A, Ozdemir O (2013) Germ-line MTHFR C677T, FV H1299R and PAI-1 5G/4G variations in breast carcinoma. Asian Pac J Cancer Prev 14:2903–2908

    Article  PubMed  Google Scholar 

  • Paydar P et al (2019) Epigenetic modulation of BRCA-1 and MGMT genes, and histones H4 and H3 are associated with breast tumors. J Cell Biochem 120:13726–13736

    Article  CAS  PubMed  Google Scholar 

  • Pooja S et al (2015) MTHFR 677C> T polymorphism and the risk of breast cancer: evidence from an original study and pooled data for 28031 cases and 31880 controls. PLoS ONE 10:e0120654

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Prasad VV, Wilkhoo H (2011) Association of the functional polymorphism C677T in the methylenetetrahydrofolate reductase gene with colorectal, thyroid, breast, ovarian, and cervical cancers. Oncol Res Treat 34:422–426

    CAS  Google Scholar 

  • Rahimi Z, Bozorgi M, Rahimi Z, Shakiba E, Yari K, Jalilian N, Vaisi-Raygani A (2019) MTHFR C677T polymorphism is associated with the risk of breast cancer among Kurdish population from Western Iran. Int J Cancer Manage. https://doi.org/10.5812/ijcm.67895

    Article  Google Scholar 

  • Rai V (2014) Methylenetetrahydrofolate reductase A1298C polymorphism and breast cancer risk: a meta analysis of 33 studies. Ann Med Health Sci Res 4:841–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Khuhaprema T, Yoshida T (2010) Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case–control study in Thai women. Breast Cancer Res Treat 123:885–893

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Song A, Zhao L, Li Y, Wu L, Li Y, Liu X, Lan S (2016) Haplotypes of the MTHFR gene are associated with an increased risk of breast cancer in a Han Chinese population in Gansu province. IUBMB Life 68:526–534

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T et al (2008) One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis 29:356–362

    Article  CAS  PubMed  Google Scholar 

  • Teng Z, Wang L, Cai S, Yu P, Wang J, Gong J, Liu Y (2013) The 677C> T (rs1801133) polymorphism in the MTHFR gene contributes to colorectal cancer risk: a meta-analysis based on 71 research studies. PLoS ONE 8:e55332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tomita LY (2016) Folate and cancer: is there any association? J Inborn Errors Metab Screen 4:2326409816661357

    Article  CAS  Google Scholar 

  • Wan L, Li Y, Zhang Z, Sun Z, He Y, Li R (2018) Methylenetetrahydrofolate reductase and psychiatric diseases. Transl Psychiatry 8:1–12

    Article  CAS  Google Scholar 

  • Waseem M et al (2016) Association of MTHFR (C677T) gene polymorphism with breast cancer in North India. Biomark Cancer. https://doi.org/10.4137/BIC.S40446

    Article  PubMed  PubMed Central  Google Scholar 

  • Weiner A et al (2010) Polymorphic variants of folate metabolizing genes (C677T and A1298C MTHFR and C1420T SHMT1 and G1958A MTHFD) are not associated with the risk of breast cancer in the West Siberian Region of Russia. Mol Biol 44:720–727

    Article  CAS  Google Scholar 

  • Weiwei Z, Liping C, Dequan L (2014) Association between dietary intake of folate, vitamin B6, B12 & MTHFR, MTR Genotype and breast cancer risk. Pak J Med Sci 30:106

    PubMed  PubMed Central  Google Scholar 

  • Yip C-H (2009) Breast cancer in Asia. Cancer epidemiology. Humana Press, Totowa, pp 51–64

    Chapter  Google Scholar 

  • Yu C-P, Wu M-H, Chou Y-C, Yang T, You S-L, Chen C-J, Sun C-A (2007) Breast cancer risk associated with multigenotypic polymorphisms in folate-metabolizing genes: a nested case-control study in Taiwan. Anticancer Res 27:1727–1732

    CAS  PubMed  Google Scholar 

  • Zhang X, Liu T, Li Y, Li S (2015) Association between MTHFR 677C/T and 1298A/C gene polymorphisms and breast cancer risk. Genet Mol Res 14:230

    Article  Google Scholar 

  • Zhang J, Zhang L, Li G (2016) Association between MTHFR gene 1298A> C polymorphism and breast cancer susceptibility: a meta-analysis based on 38 case-control studies with 40,985 subjects. World J Surg Oncol 14:230

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhu B, Wu X, Zhi X, Liu L, Zheng Q, Sun G (2014) Methylenetetrahydrofolate reductase C677T polymorphism and type 2 diabetes mellitus in Chinese population: a meta-analysis of 29 case-control studies. PLoS ONE 9:e102443

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The current study was funded by a Grant Number (#22963) from the Vice-chancellor for Research, Shiraz University of Medical Sciences, Shiraz, Iran.

Funding

No funding was received.

Author information

Authors and Affiliations

  1. Dermatology Department, Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Maryam Rezaee

  2. Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran

    Hamed Akbari

  3. Department of Biochemistry, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran

    Hamed Akbari

  4. Department of Nutrition and Biochemistry, Gonabad University of Medical Sciences, Gonabad, Iran

    Mohammad Amin Momeni-Moghaddam

  5. Department of Hematology, Faculty of Allied Medicine, Bushehr University of Medical Sciences, Bushehr, Iran

    Fatemeh Moazzen

  6. Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Tehran, Iran

    Sarvenaz Salahi

  7. Department of Radiology, Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Reza Jahankhah

  8. Breast Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Sedigheh Tahmasebi

Authors
  1. Maryam Rezaee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hamed Akbari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammad Amin Momeni-Moghaddam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fatemeh Moazzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sarvenaz Salahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Reza Jahankhah
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sedigheh Tahmasebi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sedigheh Tahmasebi.

Ethics declarations

Conflict of interest

Authors declare that they have no conflicts of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Electronic supplementary material 1 (DOCX 50 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rezaee, M., Akbari, H., Momeni-Moghaddam, M.A. et al. Association of C677T (rs1081133) and A1298C (rs1801131) Methylenetetrahydrofolate Reductase Variants with Breast Cancer Susceptibility Among Asians: A Systematic Review and Meta-Analysis. Biochem Genet 59, 367–397 (2021). https://doi.org/10.1007/s10528-020-10020-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10528-020-10020-z

Keywords

Search

Navigation