V. B. ÇETİNTAŞ, Ç B AVCI, S Y SÜSLÜER, Z. EROĞLU, C. GÜNDÜZ

Meta-analiz: Türk Toplumunda MTHFR c.677C>T polimorfizmi ve kanser ilişkisi

Amaç: Global DNA hipometilasyonu hiperhomosisteinemi, MTHFR c.677C>T homozigotluğu ve kanser gelişimi ile ilişkilidir. Bu çalışmanın amacı, Türk popülasyonunda MTHFR c.677C>T polimorfizmi ve kanser riskinin meta-analiz yoluyla araştırılmasıdır. Gereç ve Yöntem: Çalışmalar, elektronik veri tabanlarının Türk popülasyonu, MTHFR C677T ve kanser riski anahtar kelimelerine odaklanılarak taranması ile belirlendi. Elde edilen verilerin meta-analizi STATA yazılım kullanılarak yapıldı. Olasılık oranı (OR) ve %95 güven aralığı (Cl) değerleri, Mantel-Haentzel istatistiği kullanılarak sabit etki modeline göre hesaplandı. Bulgular: Resesif (CC+CT vs TT), Homozigot (CC vs TT) ve Dominant (CC vs CT+TT) genetik modellerde OR değerleri sırasıyla 1.24 (%95 CI:1.013-1.524), 1.14 (%95 CI: 0.93-1.41) ve 0.97 (%95 CI: 0.869-1.090) olarak hesaplandı. TT genotipinde kanser riskinin artışı anlamlı bulundu (p=0.043). Sonuç: Elde ettiğimiz bulgular, Türk toplumunda MTHFR c.677C>T polimorfizminin kanser riskinin belirlenmesi için potansiyel bir belirteç olduğunu desteklemektedir.

Meta-analysis: Association between MTHFR c.677C>T polymorphism and cancer in the Turkish population

Global DNA hypomethylation associates with hyperhomocysteinemia, MTHFR c.677C>T homozygosity and the development of cancer. Aim: The aim of this study was to investigate the relationship of the MTHFR c.677C>T polymorphism with the risk of cancer in the Turkish population via meta-analysis. Materials and Methods: Studies were identified by searching electronic literature, focusing on the key words; Turkish population, MTHFR C677T and the risk of cancer. All data were analyzed using STATA software. Odds ratio (OR) and 95% confidence interval (Cl) values were calculated using the Mantel-Haentzel statistic according to fixed-effect model. Results: Odds ratio values for Recessive (CC+CT vs TT), Homozygous (CC vs TT) and Dominant (CC vs CT+TT) genetic models were calculated as 1.24 (95% CI: 1.013-1.524), 1.14 (95% CI: 0.93-1.41) and 0.97 (95% CI: 0.869-1.090), respectively. The risk of cancer increased significantly in the TT genotype (p=0.043). Conclusion: Our results support the finding that MTHFR c.677C>T polymorphism is a potential biomarker for cancer risk in the Turkish population.

PDF

___

1. Stern LL, Mason JB, Selhub J, Choi SW. 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 2000;9(8):849-53.
2. 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(1):111-3.
3. Ulvik A, Evensen ET, Lien EA, Hoff G, Vollset SE, Majak BM, Ueland PM. Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of colorectum. Am J Med Genet 2001;101(3):246-54.
4. 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 USA 2002;99(8):5606-11.
5. 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 USA 1997;94(7):3290-5.
6. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22(4):719-48.
7. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):629-34.
8. Higgins JP,Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21(11):1539-58.
9. Balta G, Yuksek N, Ozyurek E, Ertem U, Hicsonmez G, Altay C, Gurgey A. Characterization of MTHFR, GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood acute leukemia. Am J Hematol 2003;73(13):154-60.
10. Deligezer U, Akisik E, Dalay N. Genotyping of the MTHFR gene polymorphism, C677T in patients with leukemia by melting curve analysis. Mol Diagn 2003;7(3-4):181-5.
11. Ergul E, Sazci A, Utkan Z, Canturk NZ. Polymorphisms in the MTHFR gene are associated with breast cancer. Tumour Biol 2003;24(6):286-90.
12. Deligezer U, Akisik EE, Dalay N. Homozygosity at the C677T of the MTHFR gene is associated with increased breast cancer risk in the Turkish population. In Vivo 2005;19(5):889-93.
13. Deligezer U, Akisik EE, Yaman F, Erten N, Dalay N. MTHFR C677 T gene polymorphism in lymphoproliferative diseases. J Clin Lab Anal 2006;20(2):37-41.
14. Kafadar AM, Yilmaz H, Kafadar D, Ergen A, Zeybek U, Bozkurt N, et al. C677T gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) in meningiomas and high-grade gliomas. Anticancer Res 2006;26(3B):2445-9.
15. Taşçığlu N, Taheri S, Saatçi S, Özkul Y. Gastrointestinal sistem kanserlerinde Metilentetrahidrofolat redüktaz geni 677C-T polimorfizminin incelenmesi. Sağlık Bilimleri Dergisi 2006;15(1):41-5.
16. Timuragaoglu A, Dizlek S, Uysalgil N, Tosun O,Yamac K. Methylenetetrahydrofolate reductase C677T polymorphism in adult patients with lymphoproliferative disorders and its effect on chemotherapy. Ann Hematol 2006;85(12):863-8.
17. Hekim N, Ergen A, Yaylim I, Yilmaz H, Zeybek U, Ozturk O, Isbir T. No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer. Cell Biochem Funct 2007;25(1):115-7.
18. Özkılıç AÇ. Over kanserli hastalarda MTHFR polimorfizmi, folat, homosistein düzeyleri ve apoptoz eğilimleri. Doktora tezi 2007.
19. Zeybek U, Yaylim I, Yilmaz H, et al. Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer. Cell Biochem Funct 2007;25(4):419-22.
20. Akay S, Eroğlu Z, Akyıldız M, Kosova B, Aydın A, Topçuoğlu N. Pankreas ve kolanjiyoselüler kanserlerinde Metilentetrahidrofolat redüktaz gen polimorfizmi. Haydarpaşa Numune EAH Tıp Derg 2008;48(3):208-12.
21. Ozger H, Kilicoglu O, Yilmaz H, Ergen HA, Yaylim I, Zeybek U, Isbir T. Methylenetetrahydrofolate reductase C677T gene polymorphism in osteosarcoma and chondrosarcoma patients. Folia Biol (Praha) 2008;54(2):53-7.
22. Muslumanoglu MH, Tepeli E, Demir S, Uludag A, Uzun D, Atli E. et al. The analysis of the relationship between A1298C and C677T polymorphisms of the MTHFR gene with prostate cancer in Eskisehir population. Genet Test Mol Biomarkers 2009;13(5):641-5.
23. Çimen YC. Rahim ağzı, yumurtalık ve over kanserli oldularda p53 72. kodon ve MTHFR C677T polimorfizminin PZR ve RFLP analizi ile araştırılması. Yüksek lisans tezi 2010.
24. Arslan S, Karadayi S, Yildirim ME, Ozdemir O, Akkurt I. The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk. Mol Biol Rep 2011;38(2):991-6.
25. Ekiz F, Ormeci N, Coban S, Karabulut HG, Aktas B, Tukun A. et al. Association of methylenetetrahydrofolate reductase C677T-A1298C polymorphisms with risk for esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Dis Esophagus 2012;25(5):437-41.
26. Izmirli M, Inandiklioglu N, Abat D, Alptekin D, Demirhan O, Tansug Z, Bayazit Y. MTHFR Gene Polymorphisms in Bladder Cancer in the Turkish Population. Asian Pac J Cancer Prev 2011;12(7):1833-5.
27. Kosova B, Özel R, Kaymaz BT, Aktan Ç, Çetintaş VB, Şen S, Çal Ç. Effects of the Catechol-O-Methyltransferase Val108/158Met and Methylenetetrahydrofolate Reductase C677T Gene Polymorphisms on Prostate Cancer Susceptibility. Turkiye Klinikleri J Med Sci 2011;31(4):943-50.
28. Kucukhuseyin O, Kurnaz O, Akadam-Teker AB, Narter F, Yilmaz-Aydogan H, Isbir T. Effects of the MTHFR C677T Polymorphism on Prostate Specific Antigen and Prostate Cancer. Asian Pac J Cancer Prev 2011;12(9):2275-8.
29. Onur E, Kurdal AT, Tugrul B, Iskesen I, Dundar P, Taneli F. et al. Is genetic screening necessary for determining the possibility of venous thromboembolism in cancer patients? Med Princ Pract 2012;21(2):160-3.
30. Akgöz S, Ercan İ, Kan İ. Meta-analizi. Uludağ Üniversitesi Tıp Fakültesi Dergisi 2004;30(2):107-12.
31. Dong X, Wu J, Liang P, Li J, Yuan L,Liu X. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer: a meta-analysis. Arch Med Res 2010;41(2):125-33.
32. Zacho J, Yazdanyar S, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. Hyperhomocysteinemia, methylenetetrahydrofolate reductase c.677C>T polymorphism and risk of cancer: cross-sectional and prospective studies and meta-analyses of 75,000 cases and 93,000 controls. Int J Cancer 2011;128(3):644-52.
33. Pereira TV, Rudnicki M, Pereira AC, Pombo-de-Oliveira MS, Franco RF. 5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2006;15(10):1956-63.
34. Yan J, Yin M, Dreyer ZE, et al. A meta-analysis of MTHFR C677T and A1298C polymorphisms and risk of acute lymphoblastic leukemia in children. Pediatr Blood Cancer 2012;58(4):513-8.
35. Jones PA. Overview of cancer epigenetics. Semin Hematol 2005;42(3Suppl):S3-8.
36. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003;349(21):2042-54.
37. Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 2001;22(4):195-201.
38. Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP. Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol 2006;163(4):300-9.
39. Yin M, Dong L, Zheng J, Zhang H, Liu J, Xu Z. Meta analysis of the association between MTHFR C677T polymorphism and the risk of congenital heart defects. Ann Hum Genet 2012;76(1):9-16.