A literature review of MTHFR (C677T and A1298C polymorphisms) and cancer risk

Schwann B, Rozen R (2001) Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. Am J Pharmacogenomics 1(3):189–201 Goyette P, Pai A, Milos R et al (1998) Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome 9(8):571–582 Goyette P, Rozen R (2000) The thermolabile variant 677C→T can further reduce activity when expressed in cis with severe mutations for human methylenetetrahydrofolate reductase. Hum Mutat 16(2):132–138 Robien K, Ulrich CM (2003) 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemiol 157(7):571–582 Yang QH, Botto LD, Gallagher M et al (2008) Prevalence and effects of gene–gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank. Am J Clin Nutr 88(1):232–246 Boushey CJ, Beresford SA, Omenn GS et al (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274(13):1049–1057 Ueland PM, Refsum H, Stabler SP et al (1993) Total homocysteine in plasma or serum: methods and clinical applications. Clin Chem 39(9):1764–1779 Sazci A, Ergül E, Güzelhan Y et al (2003) Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia. Brain Res Mol Brain Res 117(1):104–107 Kupferminc MJ, Eldor A, Steinman N et al (1999) Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 340(1):9–13 Mills JL, Kirke PN, Molloy AM et al (1999) Methylenetetrahydrofolate reductase thermolabile variant and oral clefts. Am J Med Genet 86(1):71–74 Wenstrom KD, Johanning GL, Johnston KE et al (2001) Association of the C677T methylenetetrahydrofolate reductase mutation and elevated homocysteine levels with congenital cardiac malformations. Am J Obstet Gynecol 184(5):806–812 Qiu LX, Zhang J, Li WH et al (2011) Lack of association between methlenetetrahydrofolate reductase gene A1298C polymorphism and breast cancer susceptibility. Mol Biol Rep 38(4):2295–2299 Mohammad NS, Yedluri R, Addepalli P et al (2011) Aberrations in one-carbon metabolism induce oxidative DNA damage in sporadic breast cancer. Mol Cell Biochem 349(1–2):159–167 Huang MY, Wang YH, Chen FM et al (2008) Multiple genetic polymorphisms of GSTP1 313AG, MDR1 3435CC, and MTHFR 677CC highly correlated with early relapse of breast cancer patients in Taiwan. Ann Surg Oncol 15(3):872–880 Alshatwi AA (2010) Breast cancer risk, dietary intake and methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms. Food Chem Toxicol 48(7):1881–1885 Perel’muter VM, Zav’ialova MV, Vtorushin SV et al (2008) Genetic and clinical and pathological characteristics of breast cancer in premenopausal and postmenopausal women. Adv Gerontol 21(4):643–653 Suzuki T, Matsuo K, Hirose K et al (2008) One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis 29(2):356–362 Maruti SS, Ulrich CM, Jupe ER et al (2009) MTHFR C677T and postmenopausal breast cancer risk by intakes of one-carbon metabolism nutrients: a nested case-control study. Breast Cancer Res 11(6):R91 Ericson UC, Ivarsson MI, Sonestedt E et al (2009) Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele. Am J Clin Nutr 90(5):1380–1389 Batschauer AP, Cruz NG, Oliveira VC et al (2011) HFE, MTHFR, and FGFR4 genes polymorphisms and breast cancer in Brazilian women. Mol Cell Biochem 357(1–2):247–253 Prasad VV, Wilkhoo H (2011) Association of the functional polymorphism C677T in the methylenetetrahydrofolate reductase gene with colorectal, thyroid, breast, ovarian and cervical cancers. Onkologie 34(8–9):422–426 Eroglu A, Karabıyık A, Akar N (2012) The association of protease activated receptor 1 gene -506 I/D polymorphism with disease-free survival in breast cancer patients. Ann Surg Oncol 19(4):1365–1369 Ziva Cerne J, Stegel V, Gersak K et al (2011) Lack of association between methylenetetrahydrofolate reductase genetic polymorphisms and postmenopausal breast cancer risk. Mol Med Report 4(1):175–179 Knechtel G, Hofmann G, Gerger A et al (2010) Analysis of common germline polymorphisms as prognostic factors in patients with lymph node-positive breast cancer. J Cancer Res Clin Oncol 136(12):1813–1819 Xu X, Gammon MD, Wetmur JG et al (2008) B-vitamin intake, one-carbon metabolism, and survival in a population-based study of women with breast cancer. Cancer Epidemiol Biomarkers Prev 17(8):2109–2116 Lewis SJ, Harbord RM, Harris R et al (2006) Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk. J Natl Cancer Inst 98(22):1607–1622 Hekim N, Ergen A, Yaylim I et al (2007) No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer. Cell Biochem Funct 25(1):115–117 Yu CP, Wu MH, Chou YC et al (2007) Breast cancer risk associated with multigenotypic polymorphisms in folate-metabolizing genes: a nested case-control study in Taiwan. Anticancer Res 27(3B):1727–1732 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(3):885–893 Tao MH, Shields PG, Nie J et al (2009) DNA promoter methylation in breast tumors: no association with genetic polymorphisms in MTHFR and MTR. Cancer Epidemiol Biomarkers Prev 18(3):998–1002 Martin YN, Olson JE, Ingle JN et al (2006) Methylenetetrahydrofolate reductase haplotype tag single-nucleotide polymorphisms and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 15(11):2322–2324 Vaĭner AS, Boiarskikh UA, Voronina EN et al (2010) Polymorphic variants of folate metabolizing genes (C677T and A1298C MTHFR, C1420T SHMT1 and G1958A MTHFD) are not associated with the risk of breast cancer in West Siberian Region of Russia. Mol Biol 44(5):816–823 Ma E, Iwasaki M, Kobayashi M et al (2009) Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Japan. Nutr Cancer 61(4):447–456 Ferroni P, Palmirotta R, Martini F et al (2009) Determinants of homocysteine levels in colorectal and breast cancer patients. Anticancer Res 29(10):4131–4138 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(10):2565–2571 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(3):585–593 Mir MM, Dar JA, Dar NA et al (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(1):3–14 Guillem VM, Collado M, Terol MJ et al (2007) Role of MTHFR (677, 1298) haplotype in the risk of devoloping secondary leukemia after treatment of breast cancer and hematological malignancies. Leukemia 21(7):1413–1422 Martin DN, Boersma BJ, Howe TM et al (2006) Association of MTHFR gene polymorphisms with breast cancer survival. BMC Cancer 6:257 Jakubowska A, Gronwald J, Menkiszak J et al (2007) Methylenetetrahydrofolate reductase polymorphisms modify BRCA1-associated breast and ovarian cancer risks. Breast Cancer Res Treat 104(3):299–308 Chou YC, Wu MH, Yu JC 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(11):2295–2300 Stevens VL, McCullough ML, Pavluck AL et al (2007) Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence. Cancer Epidemiol Biomarkers Prev 16(6):1140–1147 Pepe C, Guidugli L, Sensi E et al (2007) Methyl group metabolism gene polymorphisms as modifier of breast cancer risk in Italian BRCA1/2 carriers. Breast Cancer Res Treat 103(1):29–36 Ericson U, Sonestedt E, Ivarsson MI et al (2009) Folate intake, methylenetetrahydrofolate reductase polymorphisms, and breast cancer risk in women from the Malmö Diet and Cancer cohort. Cancer Epidemiol Biomarkers Prev 18(4):1101–1110 Gao CM, Tang JH, Cao HX et al (2009) MTHFR polymorphisms, dietary folate intake and breast cancer risk in Chinese women. J Hum Genet 54(7):414–418 Papandreou CN, Doxani C, Zdoukopoulos N et al (2012) Evidence of association between methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a candidate gene-association study in a South-eastern European population. DNA Cell Biol 31(2):193–198 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(5A):2807–2811 Cui LH, Song Y, Si H et al (2011) Folate metabolism-related gene polymorphisms and susceptibility to primary liver cancer in North China. Med Oncol. doi:10.1007/s12032-011-0066-y Mu LN, Cao W, Zhang ZF et al (2007) Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary hepatocellular carcinoma (HCC) in a Chinese population. Cancer Causes Control 18(6):665–675 Zhu ZZ, Cong WM, Liu SF et al (2006) A study on the association of MTHFR C677T polymorphism with genetic susceptibility to hepatocellular carcinoma. Zhonghua Gan Zang Bing Za Zhi 14(3):196–198 Suzuki T, Matsuo K, Sawaki A et al (2008) Alcohol drinking and one-carbon metabolism-related gene polymorphisms on pancreatic cancer risk. Cancer Epidemiol Biomarkers Prev 17(10):2742–2747 Nisevic I, Dinic J, Nikolic A et al (2008) MTHFR C677T polymorphism in chronic pancreatitis and pancreatic adenocarcinoma. Cell Biochem Funct 26(6):659–663 Wang L, Lin DX, Lu XH et al (2006) Study on the relations between genetic polymorphisms in methylenetetrahydrofolate reductase, methionine synthase and the risk of pancreatic cancer. Zhonghua Liu Xing Bing Xue Za Zhi 27(1):50–54 Qin JM, Wang XM, Chen B et al (2008) Study on the ingestion of folate and polymorphism of MTHFR C677T with esophageal cancer in Xinjiang Kazakh. Zhonghua Liu Xing Bing Xue Za Zhi 29(1):30–33 Liu YX, Wang B, Wan MH et al (2011) Meta-analysis of the relationship between the methylenetetrahydrofolate reductase C677T genetic polymorphism, folate intake and esophageal cancer. Asian Pac J Cancer Prev 12(1):247–252 Qin JM, Yang L, Chen B et al (2008) Interaction of methylenetetrahydrofolate reductase C677T, cytochrome P450E1 polymorphism and environment factors in esophageal cancer in Kazakh population. World J Gastroenterol 14(45):6986–6992 Li D, Diao Y, Li H et al (2008) Association of the polymorphisms of MTHFR C677T, VDR C352T, and MPO G463A with risk for esophageal squamous cell dysplasia and carcinoma. Arch Med Res 39(6):594–600 Umar M, Upadhyay R, Khurana R et al (2010) Evaluation of MTHFR 677C > T polymorphism in prediction and prognosis of esophageal squamous cell carcinoma: a case-control study in a northern Indian population. Nutr Cancer 62(6):743–749 Lu C, Xie H, Wang F et al (2011) Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in association with the prognosis of esophageal squamous cell carcinoma. BMC Cancer 11:91 Zeybek U, Yaylim I, Yilmaz H et al (2007) Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer. Cell Biochem Funct 25(4):419–422 Boccia S, Gianfagna F, Persiani R et al (2007) Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and susceptibility to gastric adenocarcinoma in an Italian population. Biomarkers 12(6):635–644 Li S, Ji M, He N et al (2007) Application of microarray-based method for methylenetetrahydrofolate reductase (MTHFR) polymorphisms in the risk of gastric carcinoma in east China population. J Nanosci Nanotechnol 7(9):3245–3249 Mu LN, Cao W, Zhang ZF et al (2007) Polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR), fruit and vegetable intake, and the risk of stomach cancer. Biomarkers 12(1):61–75 Zhang FF, Terry MB, Hou L et al (2007) Genetic polymorphisms in folate metabolism and the risk of stomach cancer. Cancer Epidemiol Biomarkers Prev 16(1):115–121 Neves Filho EH, Alves MK, Lima VP et al (2010) MTHFR C677T polymorphism and differential methylation status in gastric cancer: an association with Helicobacter pylori infection. Virchows Arch 457(6):627–633 Götze T, Röcken C, Röhl FW et al (2007) Gene polymorphisms of folate metabolizing enzymes and the risk of gastric cancer. Cancer Lett 251(2):228–236 Zúñiga-Noriega JR, Velazco-Campos Mdel R, Aguirre-Rodríguez A et al (2007) C677T polymorphism of the MTHFR gene and the risk of developing distal gastric cancer in a Mexican population. Rev Gastroenterol Mex 72(4):355–358 DeRe V, Cannizzaro R, Canzonieri V et al (2010) MTHFR polymorphisms in gastric cancer and in first-degree relatives of patients with gastric cancer. Tumour Biol 31(1):23–32 Lin D, Li H, Tan W et al (2007) Genetic polymorphisms in folate-metabolizing enzymes and risk of gastroesophageal cancers: a potential nutrient-gene interaction in cancer development. Forum Nutr 60:140–145 Wang L, Ke Q, Chen W et al (2007) Polymorphisms of MTHFD, plasma homocysteine levels, and risk of gastric cancer in a high-risk Chinese population. Clin Cancer Res 13(8):2526–2532 Cui LH, Shin MH, Kweon SS et al (2010) Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer in a Korean population. BMC Cancer 10:236 Wang Y, Guo W, He Y et al (2007) Association of MTHFR C677T and SHMT(1) C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China. Cancer Causes Control 18(2):143–152 Ko KH, Kim NK, Yim DJ et al (2006) Polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR C677T) and thymidylate synthase enhancer region (TSER) as a risk factor of cholangiocarcinoma in a Korean population. Anticancer Res 26(6B):4229–4233 Graziano F, Kawakami K, Ruzzo A et al (2006) Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at-risk Italian population. Int J Cancer 118(3):628–632 Lacasaña-Navarro M, Galván-Portillo M, Chen J et al (2006) Methylenetetrahydrofolate reductase 677C > T polymorphism and gastric cancer susceptibility in Mexico. Eur J Cancer 42(4):528–533 Promthet SS, Pientong C, Ekalaksananan T et al (2010) Risk factors for colon cancer in Northeastern Thailand: interaction of MTHFR codon 677 and 1298 genotypes with environmental factors. J Epidemiol 20(4):329–338 Haghighi MM, Radpour R, Mahmoudi T et al (2009) Associaiton between MTHFR polymorphism (C677T) with nonfamilial colorectal cancer. Oncol Res 18(2–3):57–63 Levine AJ, Figueiredo JC, Lee W et al (2010) Genetic variability in the MTHFR gene and colorectal cancer risk using the colorectal cancer family registry. Cancer Epidemiol Biomarkers Prev 19(1):89–100 El Awady MK, Karim AM, Hanna LS et al (2009) Methylenetetrahydrofolate reductase gene polymorphisms and the risk of colorectal carcinoma in a sample of Egyptian individuals. Cancer Biomark 5(6):233–240 Osian G, Procopciuc L, Vlad L (2007) MTHFR polymorphisms as prognostic factors in sporadic colorectal cancer. J Gastrointestin Liver Dis 16(3):251–256 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(5):483–489 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(2):203–208 Wang J, Gajalakshmi V, Jiang J et al (2006) 5,10-methylenetetrahydrofolate reductase codon 677 and 1298 genetic polymorphisms and environmental factors with reference to susceptibility to colorectal cancer: a case-control study in an Indian population. Int J Cancer 118(4):991–997 Iacopetta B, Heyworth J, Girschik J et al (2009) The MTHFR C677T and DeltaDNMT3B C-149T polymorphisms confer different risks for right- and left-sided colorectal cancer. Int J Cancer 125(1):84–90 Komlosi V, Hitre E, Pap E et al (2010) SHMT1 1420 and MTHFR 677 variants are associated with rectal but not colon cancer. BMC Cancer 10:525 Derwinger K, Wettergren Y, Odin E et al (2009) A study of the MTHFR gene polymorphism C677T in colorectal cancer. Clin Colorectal Cancer 8(1):43–48 Rodrigues JO, Galbiatti AL, Ruiz MT et al (2010) Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene and risk of head and neck squamous cell carcinoma. Braz J Otorhinolaryngol 76(6):776–782 Fard-Esfahani P, Fard-Esfahani A, Saidi P et al (2011) An increased risk of differentiated thyroid carcinoma in Iran with the 677C → T homozygous polymorphism in the MTHFR Gene. Cancer Epidemiol 35(1):56–58 Supic G, Jovic N, Kozomara R et al (2011) Interaction between the MTHFR C677T polymorphism and alcohol-impact on oral cancer risk and multiple DNA methylation of tumor-related genes. J Dent Res 90(1):65–70 Solomon PR, Selvam GS, Shanmugam G (2008) Polymorphism in ADH and MTHFR genes in oral squamous cell carcinoma of Indians. Oral Dis 14(7):633–639 Suzuki T, Matsuo K, Hasegawa Y et al (2007) One-carbon metabolism-related gene polymorphisms and risk of head and neck squamous cell carcinoma: case-control study. Cancer Sci 98(9):1439–1446 Vairaktaris E, Yapijakis C, Kessler P et al (2006) Methylenetetrahydrofolate reductase polymorphism and minor increase of risk for oral cancer. J Cancer Res Clin Oncol 132(4):219–222 Sailasree R, Nalinakumari KR, Sebastian P et al (2011) Influence of methylenetetrahydrofolate reductase polymorphisms in oral cancer patients. J Oral Pathol Med 40(1):61–66 Tsai CW, Hsu CF, Tsai MH et al (2011) Methylenetetrahydrofolate reductase (MTHFR) genotype, smoking habit, metastasis and oral cancer in Taiwan. Anticancer Res 31(6):2395–2399 Boccia S, Boffetta P, Brennan P et al (2009) Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer. Cancer Lett 273(1):55–61 Galbiatti AL, Ruiz MT, Rodrigues JO et al (2012) Polymorphisms and haplotypes in methylenetetrahydrofolate reductase gene and head and neck squamous cell carcinoma risk. Mol Biol Rep 39(1):635–643 Cao Y, Miao XP, Huang MY et al (2010) Polymorphisms of methylenetetrahydrofolate reductase are associated with a high risk of nasopharyngeal carcinoma in a smoking population from southern China. Mol Carcinog 49(11):928–934 Ni X, Tai J, Ma LJ et al (2008) Association between genetic polymorphisms in methylenetetrahydrofolate reductase and risk of laryngeal squamous cell carcinoma. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 43(6):435–438 Kruszyna Ł, Lianeri M, Rydzanicz M et al (2010) Polymorphic variants of folate metabolism genes and the risk of laryngeal cancer. Mol Biol Rep 37(1):241–247 Siraj AK, Ibrahim M, Al-Rasheed M et al (2008) Polymorphisms of selected xenobiotic genes contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population. BMC Med Genet 9:61 Liu CS, Tsai CW, Hsia TC et al (2009) Interaction of methylenetetrahydrofolate reductase genotype and smoking habit in Taiwanese lung cancer patients. Cancer Genomics Proteomics 6(6):325–329 Arslan S, Karadayi S, Yildirim ME et al (2011) The association between methylenetetrahydrofolate reductase gene polymorphism and lung cancer risk. Mol Biol Rep 38(2):991–996 Liu H, Jin G, Wang H et al (2008) Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population. Lung Cancer 61(1):21–29 Suzuki T, Matsuo K, Hiraki A et al (2007) Impact of one-carbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study. Carcinogenesis 28(8):1718–1725 Kiyohara C, Horiuchi T, Takayama K et al (2011) Methylenetetrahydrofolate reductase polymorphisms and interaction with smoking and alcohol consumption in lung cancer risk: a case-control study in a Japanese Population. BMC Cancer 11:459 Matakidou A, El Galta R, Rudd MF et al (2007) Prognostic significance of folate metabolism polymorphisms for lung cancer. Br J Cancer 97(2):247–252 Hung RJ, Hashibe M, McKay J et al (2007) Folate-related genes and the risk of tobacco-related cancers in Central Europe. Carcinogenesis 28(6):1334–1340 Cui LH, Shin MH, Kim HN et al (2011) Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population. BMC Med Genet 12:28 Gemignani F, Landi S, Szeszenia-Dabrowska N et al (2007) Development of lung cancer before the age of 50: the role of xenobiotic metabolizing genes. Carcinogenesis 28(6):1287–1293 Ruiz-Argüelles GJ, Coconi-Linares LN, Garcés-Eisele J et al (2007) Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico. Hematology 12(5):387–391 Giovannetti E, Ugrasena DG, Supriyadi E et al (2008) Methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase promoter (TSER) polymorphisms in Indonesian children with and without leukemia. Leuk Res 32(1):19–24 Tong N, Fang Y, Li J et al (2010) Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolatereductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese population. Cancer Sci 101(3):782–786 Pietrzyk JJ, Bik-Multanowski M, Balwierz W et al (2009) Additional genetic risk factor for death in children with acute lymphoblastic leukemia: a common polymorphism of the MTHFR gene. Pediatr Blood Cancer 52(3):364–368 Alcasabas P, Ravindranath Y, Goyette G et al (2008) 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the risk of acute lymphoblastic leukemia (ALL) in Filipino children. Pediatr Blood Cancer 51(2):178–182 Kim HN, Kim YK, Lee IK et al (2009) Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies. Leuk Res 33(1):82–87 Imanishi H, Okamura N, Yagi M et al (2007) Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma. J Hum Genet 52(2):166–171 Chen BA, Jiang N, Ji MJ et al (2006) A new method for 5,10-methylenetetrahydrofolate reductase single nucleotide polymorphisms genotyping used to study susceptibility of hematological malignancy. Zhongguo Shi Yan Xue Ye Xue Za Zhi 14(6):1069–1077 Bolufer P, Barragan E, Collado M et al (2006) Influence of genetic polymorphisms on the risk of developing leukemia and on disease progression. Leuk Res 30(12):1471–1491 Robien K, Bigler J, Yasui Y et al (2006) Methylenetetrahydrofolate reductase and thymidylate synthase genotypes and risk of acute graft-versus-host disease following hematopoietic cell transplantation for chronic myelogenousleukemia. Biol Blood Marrow Transplant 12(9):973–980 Zanrasso CW, Hatagima A, Emerenciano M et al (2006) The role of methylenetetrahydrofolate reductase in acute lymphoblastic leukemia in a Brazilian mixed population. Leuk Res 30(4):477–481 Reddy H, Jamil K (2006) Polymorphisms in the MTHFR gene and their possible association with susceptibility to childhood acute lymphocytic leukemia in an Indian population. Leuk Lymphoma 47(7):1333–1339 Koppen IJ, Hermans FJ, Kaspers GJ (2010) Folate related gene polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia. Br J Haematol 148(1):3–14 Krull KR, Brouwers P, Jain N et al (2008) Folate pathway genetic polymorphisms are related to attention disorders in childhood leukemia survivors. J Pediatr 152(1):101–105 Thomas P, Fenech M (2008) Methylenetetrahydrofolate reductase, common polymorphisms, and relation to disease. Vitam Horm 79:375–392 Zintzaras E, Koufakis T, Ziakas PD et al (2006) A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia. 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Eur J Epidemiol 21(12):885–886 Sood S, Das R, Trehan A et al (2010) Methylenetetrahydrofolate reductase gene polymorphisms: association with risk for pediatric acute lymphoblastic leukemia in north Indians. Leuk Lymphoma 51(5):928–932 de Jonge R, Tissing WJ, Hooijberg JH et al (2009) Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood 113(10):2284–2289 Yan J, Yin M, Dreyer ZE et al (2012) A meta-analysis of MTHFR C677T and A1298C polymorphisms and risk of acute lymphoblastic leukemia in children. Pediatr Blood Cancer 58(4):513–518 Benetatos L, Dasoula A, Hatzimichael E et al (2011) Polo-like kinase 2 (SNK/PLK2) is a novel epigenetically regulated gene in acute myeloid leukemia and myelodysplastic syndromes: genetic and epigenetic interactions. Ann Hematol 90(9):1037–1045 Karathananis NV, Stiakaki E, Goulielmos GN et al (2011) The role of the methylenetetrahydrofolate reductase 677 and 1298 polymorphisms in Cretan children with acute lymphoblastic leukemia. Genet Test Mol Biomarkers 15(1–2):5–10 Sadananda Adiga MN, Chandy S, Ramachandra N et al (2010) Methylenetetrahydrofolate reductase gene polymorphisms and risk of acute lymphoblastic leukemia in children. Indian J Cancer 47(1):40–45 Kamel AM, Moussa HS, Ebid GT et al (2007) Synergistic effect of methyltetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphism as risk modifiers of pediatric acute lymphoblastic leukemia. J Egypt Natl Canc Inst 19(2):96–105 Oh D, Kim NK, Jang MJ et al (2007) Association of the 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) polymorphisms in Korean patients with adult acute lymphoblastic leukemia. 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