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Tumor Biology
Published in: Tumor Biology 3/2016

01-03-2016 | Original Article

Polymorphisms of 5,10-methylenetetrahydrofolate reductase and thymidylate synthase, dietary folate intake, and the risk of leukemia in adults

Authors: Ping Liu, Min Zhang, Xing Xie, Jie Jin, C D’Arcy J Holman

Published in: Tumor Biology | Issue 3/2016

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Abstract

The 5,10-methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) are critical enzymes in folate metabolism. Previous studies have reported conflicting results on the associations between MTHFR/TS polymorphisms and adult leukemia risk, which may due to the lack of information on folate intake. We investigated the risks of adult leukemia with genetic polymorphisms of folate metabolic enzymes (MTHFR C677T, A1298C, and TS) and evaluated if the associations varied by dietary folate intake from a multicenter case-control study conducted in Chinese. This study comprised 442 incident adult leukemia cases and 442 outpatient controls, individually matched to cases by gender, birth quinquennium, and study site. Genotypes were determined by a polymerase chain reaction (PCR) or PCR-based restriction fragment length polymorphism assay. Dietary folate intake was assessed by face-to-face interviews using a validated food-frequency questionnaire. The MTHFR 677TT genotype conferred a significant higher risk of leukemia in males than in females and exhibited an increased risk of acute myeloid leukemia (AML) but a decreased risk of acute lymphoblastic leukemia (ALL). The MTHFR 1298AC genotype appeared to decrease the risks of leukemia in both genders, in AML and ALL. Stratified analysis by dietary folate intake showed the increased risks of leukemia with the MTHFR 677TT and TS 2R3R/2R2R genotypes were only significant in individuals with low folate intake. A significant interaction between TS polymorphism and dietary folate intake was observed (P = 0.03). This study suggests that dietary folate intake and gender may modify the associations between MTHFR/TS polymorphisms and adult leukemia risk.
Literature
1.
Gilliland DG. Molecular genetics of human leukemia. Leukemia. 1998;12:S7–S12.PubMed
2.
Robien K, Ulrich CM. 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemiol. 2003;157:571–82.CrossRefPubMed
3.
4.
Cole P, Rodu B. Descriptive epidemiology: cancer statistics. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 228–41.
5.
Duthie SJ. Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull. 1999;55:578–92.CrossRefPubMed
6.
Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A. 1997;94:3290–5.CrossRefPubMedPubMedCentral
7.
Liu P, Holman CD, Jin J, Zhang M. Diet and risk of adult leukemia: a multicenter case-control study in China. Cancer Causes Control. 2015;26:1141–51.CrossRefPubMed
8.
Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111–3.CrossRefPubMed
9.
van der Put NM, Gabreels F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62:1044–51.CrossRefPubMedPubMedCentral
10.
Weisberg I, Tran P, Christensen B, et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64:169–72.CrossRefPubMed
11.
Kaneda S, Takeishi K, Ayusawa D, et al. Role in translation of a triple tandemly repeated sequence in the 5′-untranslated region of human thymidylate synthase mRNA. Nucleic Acids Res. 1987;15:1259–70.CrossRefPubMedPubMedCentral
12.
Horie N, Aiba H, Oguro K, et al. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct. 1995;20:191–7.CrossRefPubMed
13.
Lehman NL. Future potential of thymidylate synthase inhibitors in cancer therapy. Expert Opin Investig Drugs. 2002;11:1775–87.CrossRefPubMed
14.
Li SY, Ye JY, Liang EY, et al. Association between MTHFR C677T polymorphism and risk of acute lymphoblastic leukemia: a meta-analysis based on 51 case-control studies. Med Sci Monit. 2015;21:740–8.CrossRefPubMedPubMedCentral
15.
Xiao Y, Deng TR, Su CL, Shang Z. Methylenetetrahydrofolate reductase polymorphisms and susceptibility to acute lymphoblastic leukemia in a Chinese population: a meta-analysis. Oncol Res Treat. 2014;37:576–82.CrossRefPubMed
16.
17.
Li B, Zhang J, Wang L, et al. MTHFR genetic polymorphisms may contribute to the risk of chronic myelogenous leukemia in adults: a meta-analysis of 12 genetic association studies. Tumour Biol. 2014;35:4233–45.CrossRefPubMed
18.
Weng Y, Zhang J, Tang X, et al. Thymidylate synthase polymorphisms and hematological cancer risk: a meta-analysis. Leuk Lymphoma. 2012;53:1345–51.CrossRefPubMed
19.
Shu XO, Yang G, Jin F, et al. Validity and reproducibility of the food frequency questionnaire used in the Shanghai Women’s Health Study. Eur J Clin Nutr. 2004;58:17–23.CrossRefPubMed
20.
Zhang M, Binns CW, Lee AH. A quantitative food frequency questionnaire for women in southeast China: development and reproducibility. Asia Pac J Public Health. 2005;17:29–35.CrossRefPubMed
21.
Zhang M (2002) Dietary factors and lifestyle characteristics in the aetiology of ovarian cancer: a case-control study in China. Dissertation, Curtin University of Technology
22.
Cui YH, Liu TS, Zhuang RY, et al. Polymorphism of thymidylate synthase gene and chemosensitivity of 5-fluorouracil regimen in metastatic gastrointestinal cancer. J Dig Dis. 2009;10:118–23.CrossRefPubMed
23.
Willett W, Stampfer M. Implications of total energy intake for epidemiologic analysis. In: Willett W, editor. Nutritional epidemiology. 2nd ed. New York: Oxford University Press; 1998. p. 273–301.CrossRef
24.
National Institute of Nutrition and Food Safety, China CDC. China food composition book 1. 2nd ed. Beijing: Peking University Medical Press; 2009. p. 3–191.
25.
National Institute of Nutrition and Food Safety, China CDC. China food composition book 1. 1st ed. Beijing: Peking University Medical Press; 2002. p. 326–8.
26.
National Institute of Nutrition and Food Safety, China CDC. China food composition book 2. Beijing: Peking University Medical Press; 2005. p. 77–211.
27.
Breslow NE, Day NE. Statistical methods in cancer research. Vol. 1: The analysis of case-control studies. Lyon: IARC Scientific Publications; 1980. p. 162–91.
28.
Rothman KJ, Greenland S, Lash TL. Validity in epidemiologic studies. In: Rothman KJ, Greenland S, Lash TL, editors. Modern epidemiology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 129–34.
29.
Rota M, Porta L, Pelucchi C, et al. Alcohol drinking and risk of leukemia—a systematic review and meta-analysis of the dose-risk relation. Cancer Epidemiol. 2014;38:339–45.CrossRefPubMed
30.
Lv L, Wu C, Sun H, et al. Combined 677CC/1298AC genotypes of methylenetetrahydrofolate reductase (MTHFR) reduce susceptibility to precursor B lymphoblastic leukemia in a Chinese population. Eur J Haematol. 2010;84:506–12.CrossRefPubMed
31.
Kim HN, Kim YK, Lee IK, et al. Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies. Leuk Res. 2009;33:82–7.CrossRefPubMed
32.
Friso S, Choi SW, Girelli D, et al. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci U S A. 2002;99:5606–11.CrossRefPubMedPubMedCentral
33.
Skibola CF, Smith MT, Hubbard A, et al. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood. 2002;99:3786–91.CrossRefPubMed
34.
Ferlay J, Soerjomataram I, Ervik M, et al (2013) GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11 [Internet]. International Agency for Research on Cancer, Lyon. Available from: http://​globocan.​iarc.​fr. Accessed 26 April 2015
35.
Inoue-Choi M, Nelson HH, Robien K, et al. One-carbon metabolism nutrient status and plasma S-adenosylmethionine concentrations in middle-aged and older Chinese in Singapore. Int J Mol Epidemiol Genet. 2012;3:160–73.PubMedPubMedCentral
36.
Huang L, Deng D, Peng Z, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) are associated with susceptibility to adult acute myeloid leukemia in a Chinese population. Cancer Epidemiol. 2015;39:328–33.CrossRefPubMed
37.
Mason JB, Choi SW. Effects of alcohol on folate metabolism: implications for carcinogenesis. Alcohol. 2005;35:235–41.CrossRefPubMed
38.
Navarro-Peran E, Cabezas-Herrera J, Garcia-Canovas F, et al. The antifolate activity of tea catechins. Cancer Res. 2005;65:2059–64.CrossRefPubMed
39.
Gemmati D, De Mattei M, Catozzi L, et al. DHFR 19-bp insertion/deletion polymorphism and MTHFR C677T in adult acute lymphoblastic leukaemia: is the risk reduction due to intracellular folate unbalancing? Am J Hematol. 2009;84:526–9.CrossRefPubMed
40.
Yang L, Liu L, Wang J, et al. Polymorphisms in folate-related genes: impact on risk of adult acute lymphoblastic leukemia rather than pediatric in Han Chinese. Leuk Lymphoma. 2011;52:1770–6.CrossRefPubMed
41.
Khorshied MM, Shaheen IA, Abu Khalil RE, Sheir RE. Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in chronic myeloid leukemia: an Egyptian study. Med Oncol. 2014;31:794.CrossRefPubMed
42.
Oh D, Kim NK, Jang MJ, et al. Association of the 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) polymorphisms in Korean patients with adult acute lymphoblastic leukemia. Anticancer Res. 2007;27:3419–24.PubMed
43.
Skibola CF, Smith MT, Kane E, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci U S A. 1999;96:12810–5.CrossRefPubMedPubMedCentral
44.
Wickramasinghe SN, Fida S. Bone marrow cells from vitamin B12- and folate-deficient patients misincorporate uracil into DNA. Blood. 1994;83:1656–61.PubMed
45.
Chen J, Gammon MD, Chan W, et al. One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Res. 2005;65:1606–14.CrossRefPubMed
46.
Shrubsole MJ, Gao YT, Cai Q, 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.CrossRefPubMed
47.
Heijmans BT, Boer JM, Suchiman HE, et al. A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer. Cancer Res. 2003;63:1249–53.PubMed
Metadata
Title
Polymorphisms of 5,10-methylenetetrahydrofolate reductase and thymidylate synthase, dietary folate intake, and the risk of leukemia in adults
Authors
Ping Liu
Min Zhang
Xing Xie
Jie Jin
C D’Arcy J Holman
Publication date
01-03-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 3/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4168-6

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