Polymorphism of MDR1, MTHFR, GSTM1, GSTT1 genes and predisposition to development of childhood acute leukemia

  • Tatsiana V. Savitskaya

Abstract

The role of genetic polymorphisms in the development of cancer is still under active study, but already today accumulated data show its importance in medicine. Research in this area will not only help to better understand the mechanisms of carcinogenesis, but also to identify risk groups for each nosology and to monitor these groups for early detection of cancer.
When searching for genetic markers of oncohematological diseases, polymorphisms of genes involved in xenobiotic biotransformation systems were investigated. Molecular genetic methods were used: polymerase chain reaction and restriction analysis.
The study identifies for the first time the frequencies of MDR1, MTHFR, GSTM1, GSTT genotypes in Belarusian children. Analysis of associations of polymorphic variants of MDR1 C3435T gene with the risk of acute leukemia revealed that heterozygous individuals with the «wild-type» MDR1 C3435T allele have a reduced risk of acute leukemia development, while homozygous carriers of 2 mutant MDR1 T3435T alleles have a significant risk for both acute lymphoblastic leukemia
(ALL) and acute myeloblastic leukemia (AML) (p = 0.01 and p = 0.02, respectively).
Analysis of associations of GSTT1 gene polymorphic variants revealed that children with the «not 0» genotype had an almost 6-fold increased risk of acute leukemia compared to patients with the «0» genotype, and a significantly higher risk of AML (p = 0.003).
No statistically significant associations of MDR1 G2677T, MTHFR C677T, and GSTM1 polymorphisms with the risk of acute leukemia were found, indicating that none of these genotypes studied was a predisposition factor for this disease. Our research has shown the importance of genetic polymorphism as a factor determining susceptibility to acute leukemia. Further study of gene polymorphism and its association with various diseases will make it possible to characterize genetic features characteristic of the Belarusian population.

References

  1. Reizine NM, O’Donnell PH. Modern developments in germline pharmacogenomics for oncology prescribing. CA Cancer Journal for Clinicians. 2022;72(4):315–332. DOI: 10.3322/caac.21722.
  2. Weiss J, Kopecky K, Godwin J, Anderson J, Willman C, Moysich K, Slovak M, Hoque A, Ambrosone C. Glutathione S-transferase (GSTM1, GSTT1 and GSTA1) polymorphisms and outcomes after treatment for acute myeloid leukemia: pharmacogenetics in Southwest Oncology Group (SWOG) clinical trials. Leukemia. 2007;20(12):2169–2171. DOI: 10.1038/sj.leu.2404421.
  3. Cameron K. Etiology of acute leukemia: a review. Cancers (Basel). 2021;13(9):2256. DOI: 10.3390/cancers13092256.
  4. Illmer T, Schuler U, Thiede C, Schwarz U, Kim R, Gotthard S, Freund D, Schakel U, Ehninger G, Schaich M. MDR1 Gene Polymorphisms Affect Therapy Outcome in Acute Myeloid Leukemia Patients. Cancer Research. 2002;62:4955–4962.
  5. Bagdasaryan AA, Chubarev BB, Smolyarchuk EA, Drozdov VN, Krasnyuk II, Liu J, Ruitai F, Tse E, Shikh EV, Sukocheva OA. Pharmacogenetics of Drug Metabolism: The Role of Gene Polymorphism in the Regulation of Doxorubicin Safety. Cancers. 2022;14:5436–5441. DOI: 10.3390/cancers14215436.
  6. Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. American Journal of Clinical Nutrition. 2015;101(6):1286–1294. DOI: 10.3945/ajcn.114.099994.
  7. Robien K, Ulrich C. 2, 3 5, 10-Methylenetetrahydrofolate Reductase Polymorphisms and Leukemia Risk: A HuGE Minireview. American Journal of Epidemiology. 2003;157:571–582. DOI: 10.1093/aje/kwg024.
  8. Krajinovic M, Lamothe S, Labuda D, Lemieux-Blanchard E, Theoret T, Moghrabi A, Sinnett D. Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood. 2004;103(1):252–257. DOI: 10.1182/blood-2003-06-1794.
  9. Amromina AM, Sitnikov IA, Shaikhova DR. Vzaimosvyaz’ polimorfnykh variantov genov GSTM1, GSTT1, GSTP1 s riskom razvitiya zabolevaniy (obzor literatury) [Relationship of polymorphic variants of GSTM1, GSTT1, GSTP1 genes with the risk of disease development]. Hygiene and Sanitation. 2021;100(12):1385–1390. DOI: 10.47470/0016-9900-2021-100-12-1385-1390. Russian.
  10. Moulik NR, Parveen F, Kumar A, Agrawal S. Glutathione-S-transferase polymorphism and acute lymphoblastic leukemia (ALL) in north Indian children: a case–control study and meta-analysis. Journal Human Genetics. 2014;59:529–535. DOI: 10.1038/jhg.2014.66.
  11. Takanashi M, Mjrimoto A, Yagi A, Kuriyma K, Kano G, Imamura T, Hibi S, Todo S, Imashuku S. Impact of glutathione S-transferase gene deletion on early relapse in childhood B-precursor acute lymphoblastic leukemia. Haematologica. 2003;88:1238–1244.
  12. Rocha J, Cheng C, Liu W, Kishi S, Das S, Cook E, Sandlund J, Rubnitz J, Ribeiro R, Campana D, Pui C, Evans W, Relling M. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia Blood. 2005;105(12):4752–4758. DOI: 10.1182/blood-2004-11-4544.
  13. Ling M R. Isolation of Total Cellular DNA from Tissues and Cultured Cells. Molecular Biomethods Handbook. Totowa: Humana Press; 1996. p. 9–16.
  14. Song P, Li S, Meibohm B, Gaber A, Honaker M, Kotb M, Yates C. Detection of MDR1 single Nucleotide polymorphisms C3435T and G2677T using real-time polymerase chauin reaction: MDR1 single nucleotide polymorphism genotyping assay. AAPS PharmSciTech. 2002;4(4):89–94. DOI: 10.1208/ps040429.
  15. Schmitz C, Lindpaintner K, Verhoef P, Gaziano JM, Buring J. Genetic polymorphism of methylenetetrahydrofolate reductase and myocardial infarction. A case-control study. Circulation. 1996;94(8):1812–4. DOI: 10.1161/01.cir.94.8.1812.
  16. Chang JG, Lee LS, Chen CM, Shih MC, Wu MC, Tsai FJ, Liang DC. Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics. 2002;12(3):191–195. DOI: 10.1097/00008571-200204000-00003.
  17. Urayama K, Wiencke J, Buffler P, Chokkalingam A, Metayer C, Wiemels J. MDR1 gene variants, indoor insecticide exposure and the risk of childhood lymphoblastic leukemia. Cancer Epidemiology & Prevention. 2007;16(6):1172–1177. DOI: 10.1158/1055-9965.EPI-07-0007.
  18. Hattori H, Suminoe A, Wada M, Koga Y, Kohno K, Okamura J, Hara T, Matsuzaki A. Regulatory polymorphisms of multidrug resistance 1 (MDR1) gene are associated with the development of childhood acute lymphoblastic leukemia. Leukemia Research. 2007;31(12):1633–40. DOI: 10.1016/j.leukres.2007.04.009.
  19. Botto L, Yang Q. 5,10-Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies. American Journal of Epidemiology. 2000;151:862–877. DOI: 10.1093/oxfordjournals.aje.a010290.
  20. Kargas C, Krupa R, Walter Z. Combined genotype analysis of GSTM1 and GSTT1 polymorphisms in a Polish population. Human Biology. 2003;75(2):301–307. DOI: 10.1353/hub.2003.0033.
  21. Gra O, Glotov A, Kozhekbaeva J, Makarova O, Nasedkina T. Geneticheskiy polimorfizm GST, NAT2 i MTNFR i predraspolozhennost’ k razvitiyu ostrogo leykoza detey [Genetic polymorphism of GST, NAT2 and MTHFR and predisposition to development of childhood acute leukemia]. Molecular Biology. 2008;42(2):214–225. Russian.
  22. Barnette P, Scholl R, Blandford M, Ballard L, Tsodikov A, Magee J, Williams S, Robertson M, Ali-Osman F, Lemons R, Keller C. High-Throughput Detection of Glutathione S-Transferase Polymorphic Alleles in a Pediatric Cancer Population. Cancer Epidemiology, Biomarkers & Prevention. 2004;13:304–313.
  23. Alves S, Amorim A, Ferreira F, Norton L., Prata M. The GSTM1 and GSTT1 genetic polymorphisms and susceptibility to acute lymphoblastic leukemia in children from north Portugal. Leukemia. 2002;16:1565–1567. DOI: 10.1038/sj.leu.2402543.
  24. Cheok M, Evans W. Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy. Nature Reviews Cancer. 2006;6:117–129. DOI: 10.1038/nrc1800.
  25. de Jonge R, Tissing W, Hooijberg J, Jansen G, Kaspers G, Lindemans J, Peters G, Pieters R. Polymorphism in folat-related genes and risk of pediatric acute lymphoblastic leukemia. Blood. 2004;113(10):2284–2289. DOI: 10.1182/blood-2008-07-165928.
  26. Sakaeda T. MDR1 genotype- related pharmacokinetics: fact or fiction? Drug Metabolism and Pharmacokinetics. 2005;20(6):391–414. DOI: 10.2133/dmpk.20.391.
Published
2023-11-08
Keywords: genetic polymorphism;, xenobiotics, children, acute leukemia
How to Cite
Savitskaya, T. (2023). Polymorphism of MDR1, MTHFR, GSTM1, GSTT1 genes and predisposition to development of childhood acute leukemia. Journal of the Belarusian State University. Ecology, 2. Retrieved from https://journals.bsu.by/index.php/ecology/article/view/5928
Issue
No 2 (2023): Journal of the Belarusian State University. Ecology.
Section
Medical Ecology