Methylenetetrahydrofolate Reductase Gene Germ-Line C677T and A1298C SNPs are Associated with Colorectal Cancer Risk in the Turkish Population

  • Ozen, Filiz (Department of Medical Genetics, Faculty of Medicine, Cumhuriyet University) ;
  • Sen, Metin (Department of General Surgery, Faculty of Medicine, Cumhuriyet University) ;
  • Ozdemir, Ozturk (Department of Medical Genetics, Faculty of Medicine, Cumhuriyet University)
  • 발행 : 2014.10.11


Colorectal cancer (CRC) is the third most common cause of death due to cancer in the worldwide and the incidence is also increasing in Turkey. Our present aim was to investigate any association between germ-line methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and CRC risk in Turkey. A total of 86 CRC cases and 212 control individuals of the same ethnicity were included in the current study. Peripheral blood-DNA samples were used for genotyping by StripAssay technique, based on the reverse-hybridization principle and real-time PCR methods. Results were compared in Pearson Chi-square and multiple logistic regression models. The MTHFR 677TT (homozygous) genotype was found in 20.9% and the T allele frequency 4.2-fold increased in CRC when compared with the control group.The second SNP MTHFR 1298CC (homozygous) genotype was found in 14.0% and the C allele frequency 1.4-fold elevated in the CRC group. The current data suggest strong associations between both SNPs of germ-line MTHFR 677 C>T and 1298 A>C genotypes and CRC susceptibility in the Turkish population. Now the results need to be confirmed with a larger sample size.


  1. Blount BC, Mack MM, Wehr CM, et al (1997). Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA, 94, 3290-5.
  2. Cao HX, Gao CM, Takezaki T, et al (2008) Genetic polymorphisms of methylenetetrahydrofolate reductase and susceptibility to colorectal cancer. Asian Pac J Cancer Prev, 9, 203-8.
  3. Choi SW, Mason JB (2000). Folate and carcinogenesis: an integrated scheme. J Nutr, 130, 129 -32.
  4. Chang SC, Lin PC, Lin JK, et al (2007). Role of MTHFR polymorphisms and folate levels in different phenotypes of sporadic colorectal cancers. Int J Colorectal Dis, 22, 483-9.
  5. Cheah PY(2009). Recent advances in colorectal cancer genetics and diagnostics. Crit Rev Oncol Hematol, 69, 45-55.
  6. Chen J, Ma J, Stampfer MJ, et al (2002). Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer. Pharmacogenetics, 12, 339-42.
  7. de Kok TM, van Maanen JM (2000). Evaluation of fecal mutagenicity and colorectal cancer risk. Mutat Res, 463, 53-101.
  8. Deloughery TG, Evans A, Sadeghi A, et al (1996). Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease. Circulation, 94, 3074-8.
  9. Fang JY, Xiao SD (2003). Folic acid, polymorphism of methylgroup metabolism genes, and DNA methylation in relation to GI carcinogenesis. J Gastroenterol, 38, 821-9.
  10. Fearon ER, Vogelstein BA (1990). Genetic model for colorectal tumorigenesis. Cell, 61, 759-67.
  11. Fernandez-Peralta AM, Daimiel L, Nejda N, et al (2010). Association of polymorphisms MTHFR C677T and A1298C with risk of colorectal cancer, genetic and epigenetic characteristic of tumors, and response to chemotherapy. Int J Colorectal Dis, 25, 141-51.
  12. Friedman G, Goldschmidt N, Friedlander Y, et al (1999). A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr, 129, 1656-61.
  13. Goyette P, Aditya P, Renate M, et al (1998). Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mammalian Genome, 9, 652-6.
  14. Frosst P, Blom HJ, Milos R, et al (1995). Candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase [letter]. Nat Genet, 10, 111-3.
  15. Gallegos-Arreola MP, Garcia-Ortiz JE, Figuera LE, et al (2009). Association of the 677C>T polymorphism in the MTHFR gene with colorectal cancer in Mexican patients. Cancer Genomics Proteomics, 6, 183-8.
  16. Ge H, Zheng X, Zhao E, et al (2012). Letter to the editor: a meta-analysis of association between polymorphism of MTHFR A1298C and colorectal cancer risk. Int J Colorectal Dis, 27, 1387-8.
  17. Guerreiro CS, Carmona B, Gonçalves S, et al (2008). Risk of colorectal cancer associated with the C677T polymorphism in 5,10-methylenetetrahydrofolate reductase in Portuguese patients depends on the intake of methyl-donor nutrients. American Society for Nutrition, Am J Clin Nutr, 88, 1413-8.
  18. Huang Y, Han S, Li Y, et al (2007). Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: a meta-analysis. J Hum Genet, 52, 73-85.
  19. Izmirli M, Inandiklioglu N, Abat D, et al (2011). MTHFR gene polymorphisms in bladder cancer in the Turkish population. Asian Pac J Cancer Prev, 12,1833-35.
  20. Izmirli M (2013). A literature review of MTHFR (C677T and A1298C polymorphisms) and cancer risk. Mol Biol Rep, 40, 625-37.
  21. Kono S, Chen K (2005). Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma. Cancer Science, 96, 535-42.
  22. Nassiri M, Kooshyar MM, Roudbar Z, et al (2013). Genes and SNPs associated with non-hereditary and hereditary colorectal cancer. Asian Pac J Cancer Prev, 14, 5609-14.
  23. Kury S, Buecher B, Robiou-du-Pont S, et al (2008). Lowpenetrance alleles predisposing to sporadic colorectal cancers: a French case-controlled genetic association study. BMC Cancer, 8, 326.
  24. Li H, Xu WL, Shen HL, et al (2011). Methylenetetrahydrofolate reductase genotypes and haplotypes associated with susceptibility to colorectal cancer in an eastern Chinese Han population. Genet Mol Res, 10, 3738-46.
  25. Lightfoot TJ, Barrett JH, Bishop T, et al (2008). Methylene tetrahydrofolate reductase genotype modifies the chemopreventive effect of folate in colorectal adenoma, but not colorectal cancer. Cancer Epidemiol Biomarkers Prev, 17, 2421-30.
  26. Ozdemir O, Yenicesu GI, Silan F, et al (2012). Recurrent Pregnancy Loss and Its Relation to Combined Parental Thrombophilic Gene Mutations. Genet Test Mol Biomarkers, 16, 279-86.
  27. Ozdemir O, Silan F, Urfali M, et al (2014). Variable R.Msp1 fragmentation in genomic DNA due to DNA hypomethylation in CRF patients with MTHFR C677Tgene polymorphism: from genetics to epigenetics. Genet Test Mol Biomarkers, 6, 77-87.
  28. Pardini B, Kumar R, Naccarati A, et al (2011). MTHFR and MTRR genotype and haplotype analysis and colorectal cancer susceptibility in a case-control study from the Czech Republic. Mutat Res, 721, 74-80.
  29. Parkin DM, Bray F, Ferlay J, et al (2002). Global cancer statistics. CA Cancer J Clin, 55, 74-108.
  30. Parle-McDermott A, Mills JL, Molloy AM, et al (2006). The MTHFR 1298CC and 677TT genotypes have opposite associations with red cell folate levels. Mol Genet Metab, 88, 290-4.
  31. Stern LL, Mason JB, Selhub J, et al (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.
  32. Sameer AS, Shah ZA, Nissar S, et al (2011). Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population. Genet Mol Res, 10, 1200-10.
  33. Schwartz SM, Siscovick DS, Malinow MR, et al (1997). Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene. Circulation, 96, 412-7.
  34. Slattery ML, Potter JD, Samowitz W, et al (1999). Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev, 8, 513-8.
  35. Torre ML, Russo GT, Ragonese M, et al (2014). MTHFR C677T polymorphism, folate status and colon cancer risk in acromegalic patients. Pituitary, 17, 257-66.
  36. Ulrich CM, Bigler J, Bostick R, et al (2002). Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomas. Cancer Res, 62, 3361-4.
  37. van der Put NM, Gabreels F, Stevens EM, et al (1998). A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet, 62, 1044-51.
  38. Weisberg I, Tran P, Christensen B, et al (1998). Second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab, 64, 169-72.
  39. Yousef AM, Shomaf M, Sondra Berger S, et al (2013). Allele and genotype frequencies of the polymorphic methylenetetrahydrofolate reductase and colorectal cancer among Jordanian population. Asian Pac J Cancer Prev, 14, 4559-65.
  40. Weisberg IS, Jacques PF, Selhub J, et al (2002). The 1298A > C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis, 156, 409-15.
  41. Xu XL, Yu J, Zhang HY, et al (2004). Methylation profile of the promoter CpG islands of 31 genes that may contribute to colorectal carcinogenesis. World J Gastroenterol, 10, 3441-54
  42. Yang Z, Zhang XF, Liu HX, et al (2012). MTHFR C677T Polymorphism and colorectal cancer risk in Asians, a meta-analysis of 21 studies. Asian Pacific J Cancer Prev, 13, 1203-8.
  43. Zeybek U, Yaylim I, Yilmaz H, et al (2007). Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer. Cell Biochem Funct, 25, 419-22.
  44. Zhao J, Li W, Zhu D, et al (2014).Association of single nucleotide polymorphisms in MTHFR and ABCG2 with the different efficacy of first-line chemotherapy in metastatic colorectal cancer. Med Oncol, 31, 802.

피인용 문헌

  1. Association between MTHFR C677T Polymorphism and Risk of Prostate Cancer: Evidence from 22 Studies with 10,832 Cases and 11,993 Controls vol.16, pp.11, 2015,
  2. Relationship between Genetic Polymorphisms in MTHFR (C677T, A1298C and their Haplotypes) and the Incidence Of Breast Cancer among Jordanian Females - Case-Control Study vol.16, pp.12, 2015,
  3. Association of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with primary glaucoma in Saudi population vol.16, pp.1, 2016,
  4. Evaluation of the MTHFR C677T Polymorphism as a Risk Factor for Colorectal Cancer in Asian Populations vol.16, pp.18, 2016,
  5. Methylenetetrahydrofolate reductase C677T polymorphism and colorectal cancer susceptibility: a meta-analysis vol.37, pp.6, 2017,