Methionine Synthase Reductase A66G Polymorphism is not Associated with Breast Cancer Susceptibility - a Meta-analysis

  • Hu, Shu (Medical College, Henan University of Science and Technology) ;
  • Liu, Hong-Chao (Medical College, Henan University of Science and Technology) ;
  • Xi, Shou-Ming (Medical College, Henan University of Science and Technology)
  • Published : 2014.04.01


Background: Several studies have investigated the association between methionine synthase reductase (MTRR) A66G polymorphism and breast cancer risk, but controversial results were yielded. Therefore, we performed a meta-analysis to provide a more robust estimate of the effect of this polymorphism on susceptibility to breast cancer. Materials and Methods:Case-control studies investigating the relationship between MTRR A66G polymorphism and breast cancer risk were included by searching PubMed, EMBASE, China National Knowledge Infrastructure and Wanfang Database. Either fixed-effects or random-effects models were applied to calculate odds ratios(ORs) and 95% confidence intervals (CIs) by RevMan5.2 software. Results: A total of 9 studies bearing 7,097 cases and 7,710 controls were included in the meta-analysis. The results were that the combined ORs and 95%CIs of MTRR 66AG, GG, (AG+GG) genotypes were 0.98(0.91-1.05), 1.06(0.97-1.16) and 1.02(0.94-1.10), respectively with p=0.52, 0.19 and 0.65. We also performed subgroup analysis by specific ethnicity. The results of the combined analysis of MTRR 66AG, GG, (AG+GG) genotypes and breast cancer in Asian descent were Z=0.50, 0.53 and 0.21, with p all>0.05; for breast cancer in Caucasian descent, the results were Z=1.14, 1.65 and 0.43, with p all>0.05. Conclusions: Our findings suggested that MTRR A66G polymorphism was not associated with breast cancer susceptibility.


  1. Widschwendter M, Jones PA (2002). DNA methylation and breast carcinogenesis. Oncogene, 2, 5462-82.
  2. Stern LL, Mason JB, Selhub J, Choi SW (2000). Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev, 9, 849-53.
  3. Suzuki T, Matsuo K, Hirose K, et al (2008). One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis, 29, 356-62.
  4. Weiner AS, Boyarskikh UA, Voronina EN, et al (2012). Polymorphisms in the folate-metabolizing genes MTR, MTRR, and CBS and breast cancer risk. Cancer Epidemiol, 36, 95-100.
  5. Wilson A, Platt R, Wu Q, 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, 317-23.
  6. Xu X, Chen J (2009). One-carbon metabolism and breast cancer: an epidemiological perspective. J Genet Genomics, 36, 203-14.
  7. Xu X, Gammon MD, Zhang H, et al (2007). Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study. Carcinogenesis, 28, 1504-9.
  8. 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.
  9. Leclerc D, Wilson A, Dumas R, et al (1998). Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc Natl Acad Sci USA, 95, 3059-64.
  10. Lissowska J, Gaudet MM, Brinton LA, et al (2007). Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses. Int J Cancer, 120, 2696-703.
  11. Marmot MG, Altman DG, Cameron DA, et al (2013). The benefits and harms of breast cancer screening: an independent review. Br J Cancer, 108, 2205-40.
  12. 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, 4893-901.
  13. Naushad SM, Reddy CA, Rupasree Y, et al (2011). Cross-talk between one-carbon metabolism and xenobiotic metabolism: implications on oxidative DNA damage and susceptibility to breast cancer. Cell Biochem Biophys, 6, 715-23.
  14. Russo J, Yang X, Hu YF, et al (1998). Biological and molecular basis of human breast cancer. Front Biosci, 3, 944-60.
  15. Sangrajrang S, Sato Y, Sakamoto H, 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.
  16. Shrubsole MJ, Gao YT, Cai Q, et al (2006). MTR and MTRR polymorphisms, dietary intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev, 15, 586-8.
  17. Siegel R, Naishadham D, Jemal A (2013). Cancer statistics, 2013. CA Cancer J Clin, 63, 11-30.
  18. Kotsopoulos J, Zhang WW, Zhang S, et al (2008). Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer. Breast Cancer Res Treat, 112, 585-93.
  19. Christensen BC, Kelsey KT, Zheng S, et al (2010). Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake. PLoS Gene, 6, 1001043.
  20. Duthie SJ (2011). Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis, 34, 101-9.
  21. Gast A, Bermejo JL, Flohr T, et al (2007). Folate metabolic gene polymorphisms and childhood acute lymphoblastic leukemia: a case-control study. Leukemia, 21, 320-5.
  22. Kwak SY, Kim UK, Cho HJ, et al (2008). Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms as risk factors for hepatocellular carcinoma in a Korean population. Anticancer Res, 28, 2807-11.
  23. Beetstra S, Suthers G, Dhillon V, et al (2008). Methionine-dependence phenotype in the de novo pathway in BRCA1 and BRCA2 mutation carriers with and without breast cancer. Cancer Epidemiol Biomarkers Prev, 17, 2565-71.
  24. Burcos T, Toma M, Stavarachi M, et al (2010). MTRR polymorphism and the risk for colorectal and breast cancer in Romanian patients-a preliminary study. Chirurgia , 105, 379-82.
  25. Choi SW, Mason JB (2000). Folate and carcinogenesis: an integrated scheme. J Nutr, 130, 129-32.
  26. Lajin B, Alhaj Sakur A, Ghabreau L, Alachkar A (2012). Association of polymorphisms in one-carbon metabolizing genes with breast cancer risk in Syrian women. Tumour Biol, 33, 1133-9.
  27. Baylin SB, Esteller M, Rountree MR, et al (2001). Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet, 10, 687-92.

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