Biopolym. Cell. 2016; 32(4):279-288.
Biomedicine
The polymorphisms of genes involved in DNA methylation in patients with malignancies from West Ukraine
1Dmytruk I. M., 1Makukh H. V., 1Thyrkus M. Y., 1Kitsera N. I.
  1. State Institution "Institute of Hereditary Pathology, NAMS of Ukraine"
    31a, M. Lysenko Str., Lviv, Ukraine, 79008

Abstract

Aim. To determine a potential role of single-nucleotide polymorphisms in the genes involved in the DNA methylation process (MTHFR, MTR, TYMS) in the breast cancer risk and risk of leukemia in a case-control study from West Ukraine. Methods. Genotyping of MTHFR 677 C>T, MTR 2756 A>G and TS 3R2R, TS 3RG>C was performed in 60 patients with leukemia, 90 patients with breast cancer and in 100 persons from a control group. The molecular-genetic analysis was performed by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism analysis. A statistical analysis was conducted by Chi-square tests and odds ratio (OR) calculation. Results. We did not observe any significant difference in genotype frequencies of the MTHFR and TYMS polymorphisms between the cases and controls. The MTR 2756AA genotype frequency was significantly higher in the patients with breast cancer vs control (0.67 vs 0.50, p = 0.02) and the difference between the patients with leukemia and the control group was not statistically significant. The increased risk of breast cancer development was associated with the MTR 2756AA genotype (OR = 2.00, CI – 95 %:1.11–3.60) and the MTR 2756A allele (OR = 1.75, CI–95 %:1.08–2.84). Conclusions. Our findings show that West Ukrainian inhabitants carrying at least one MTR 2756A allele have a significantly increased risk of breast cancer.
Keywords: methylation, polymorphism, gene, leukemia, breast cancer

References

[1] Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349(21):2042-54.
[2] Choi SW, Mason JB. Folate and carcinogenesis: an integrated scheme. J Nutr. 2000;130(2):129-32.
[3] Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene. 2001;20(24):3139-55.
[4] de Vogel S, Wouters KA, Gottschalk RW, van Schooten FJ, de Goeij AF, de Bruïne AP, Goldbohm RA, van den Brandt PA, Weijenberg MP, van Engeland M. Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylation in colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2009;18(11):3086-96.
[5] Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64(3):169-72.
[6] Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111-3.
[7] Goode EL, Potter JD, Bigler J, Ulrich CM. Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev. 2004;13(1):157-62.
[8] Hubner RA, Muir KR, Liu JF, Sellick GS, Logan RF, Grainge M, Armitage N, Chau I, Houlston RS. Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence. Cancer Epidemiol Biomarkers Prev. 2006;15(9):1607-13.
[9] Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, Warren R, Tsao-Wei D, Groshen S, Lenz HJ. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1(1):65-70.
[10] Hubner RA, Muir KR, Liu JF, Sellick GS, Logan RF, Grainge M, Armitage N, Chau I, Houlston RS. Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence. Cancer Epidemiol Biomarkers Prev. 2006;15(9):1607-13.
[11] Takehara A, Kawakami K, Ohta N, Oyama K, Ota Y, Oda M, Watanabe G. Prognostic significance of the polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase gene in lung cancer. Anticancer Res. 2005;25(6C):4455-61.
[12] Hosseini M. Role of polymorphism of methyltetrahydrofolate-homocysteine methyltransferase (MTR) A2756G and breast cancer risk. Pol J Pathol. 2013;64(3):191-5.
[13] Sharp L, Little J, Schofield AC, Pavlidou E, Cotton SC, Miedzybrodzka Z, Baird JO, Haites NE, Heys SD, Grubb DA. Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett. 2002;181(1):65-71.
[14] de Cássia Carvalho Barbosa R, da Costa DM, Cordeiro DE, Vieira AP, Rabenhorst SH. Interaction of MTHFR C677T and A1298C, and MTR A2756G gene polymorphisms in breast cancer risk in a population in Northeast Brazil. Anticancer Res. 2012;32(11):4805-11.
[15] Koppen IJ, Hermans FJ, Kaspers GJ. Folate related gene polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia. Br J Haematol. 2010;148(1):3-14.
[16] Skibola CF, Smith MT, Hubbard A, Shane B, Roberts AC, Law GR, Rollinson S, Roman E, Cartwright RA, Morgan GJ. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood. 2002;99(10):3786-91.
[17] Lauten M, Asgedom G, Welte K, Schrappe M, Stanulla M. Thymidylate synthase gene polymorphism and its association with relapse in childhood B-cell precursor acute lymphoblastic leukemia. Haematologica. 2003;88(3):353-4.
[18] Makukh HV, Zastavna DV, Tyrkus MJ, et al. The manner of DNA extraction from the peripheral blood leukocytes Appl. N u200801896; Feb. 14. 2008. Date of patent aip.25.2008.
[19] Oh D, Kim NK, Jang MJ, Kim HC, Lee JH, Lee JA, Ahn MJ, Kim CS, Kim HS, Park S, Chio HS, Min YH; HOGS Investigators. Association of the 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) polymorphisms in Korean patients with adult acute lymphoblastic leukemia. Anticancer Res. 2007;27(5A):3419-24.
[20] Thirumaran RK, Gast A, Flohr T, Burwinkel B, Bartram C, Hemminki K, Kumar R. MTHFR genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemia. Blood. 2005;106(7):2590-1.
[21] de Jonge R, Tissing WJ, Hooijberg JH, Jansen G, Kaspers GJ, Lindemans J, Peters GJ, Pieters R. Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood. 2009;113(10):2284-9.
[22] Rai V. The methylenetetrahydrofolate reductase C677T polymorphism and breast cancer risk in Asian populations. Asian Pac J Cancer Prev. 2014;15(14):5853-60.
[23] Pooja S, Carlus J, Sekhar D, Francis A, Gupta N, Konwar R, Kumar S, Kumar S, Thangaraj K, Rajender S. 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. 2015;10(3):e0120654.
[24] Försti A, Angelini S, Festa F, Sanyal S, Zhang Z, Grzybowska E, Pamula J, Pekala W, Zientek H, Hemminki K, Kumar R. Single nucleotide polymorphisms in breast cancer. Oncol Rep. 2004;11(4):917-22.
[25] Kalemi TG, Lambropoulos AF, Gueorguiev M, Chrisafi S, Papazisis KT, Kotsis A. The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece. Cancer Lett. 2005;222(1):57-65.
[26] Kawakami K, Watanabe G. Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res. 2003;63(18):6004-7.
[27] Henríquez-Hernández LA, Murias-Rosales A, Hernández González A, Cabrera De León A, Díaz-Chico BN, Mori De Santiago M, Fernández Pérez L. Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: a case-control study. Oncol Rep. 2009;22(6):1425-33.
[28] Quintero-Ramos A, Gutiérrez-Rubio SA, Del Toro-Arreola A, Franco-Topete RA, Oceguera-Villanueva A, Jiménez-Pérez LM, Castro-Cervantes JM, Barragán-Ruiz A, Vázquez-Camacho JG, Daneri-Navarro A. Association between polymorphisms in the thymidylate synthase gene and risk of breast cancer in a Mexican population. Genet Mol Res. 2014;13(4):8749-56.
[29] Lightfoot TJ, Johnston WT, Painter D, Simpson J, Roman E, Skibola CF, Smith MT, Allan JM, Taylor GM; United Kingdom Childhood Cancer Study.. Genetic variation in the folate metabolic pathway and risk of childhood leukemia. Blood. 2010;115(19):3923-9.
[30] Canalle R, Silveira VS, Scrideli CA, Queiroz RG, Lopes LF, Tone LG. Impact of thymidylate synthase promoter and DNA repair gene polymorphisms on susceptibility to childhood acute lymphoblastic leukemia. Leuk Lymphoma. 2011;52(6):1118-26.
[31] Naushad SM, Pavani A, Rupasree Y, Divyya S, Deepti S, Digumarti RR, Gottumukkala SR, Prayaga A, Kutala VK. Association of aberrations in one-carbon metabolism with molecular phenotype and grade of breast cancer. Mol Carcinog. 2012;51 Suppl 1:E32-41.
[32] Lu M, Wang F, Qiu J. Methionine synthase A2756G polymorphism and breast cancer risk: a meta-analysis involving 18,953 subjects. Breast Cancer Res Treat. 2010;123(1):213-7.
[33] Weiner AS, Boyarskikh UA, Voronina EN, Selezneva IA, Sinkina TV, Lazarev AF, Petrova VD, Filipenko ML. Polymorphisms in the folate-metabolizing genes MTR, MTRR, and CBS and breast cancer risk. Cancer Epidemiol. 2012;36(2):e95-e100.
[34] Xia J, Wang Y, Zhang H, Hu Y. Association between MTR A2756G polymorphism and childhood acute lymphoblastic leukemia: a meta-analysis. Leuk Lymphoma. 2014;55(6):1388-93.