Abstract

Introduction: The glutathione S-transferase (GST) play a crucial role in detoxification of mutagens and carcinogens, including those associated with increased risk of the acute leukemia. Both GST M1 (GSTM1) and GST theta 1 (GSTT1) genes have a "null" variant allele, in which the entire gene is absent. Previous studies have revealed significant differences between populations for genotypic frequencies of glutathione S-transferase, including (GSTM1) polymorphisms in health and disease. Therefore, we aimed to test whether the GSTM1 null genotype could alter the risk to develop acute leukemia in Sudan. 

Method: Observational analytical retrospective case-control association study was conducted, over a period of five months. A total of 100 donors/patients were randomly enrolled from different hospitals in Khartoum, Sudan. For molecular analysis genomic DNA was extracted from EDTA blood samples and analyzed by allele specific PCR for demonstration of GSTM1 gene. 

Results: The data analysis revealed that GSTM1 null genotype is demonstrated in 58% of cases (58% males and 42% females) and in 41% of control subjects (70% males and 30% females). It was observable that the GSTM1 null genotype was higher in cases compared to controls (odd ratio = 1.915, 95% CI 0.8629 to 4.251). However, the difference showed no significant association between GSTM1 Null and acute leukemia (P = 0.1085). The frequency of GSTM1 null genotype in AML-subtype was significantly higher than ALL- subtype (P = 0.0015). 

Conclusion: Our findings came up without statistical significant influence of GSTM1 null genotype on the risk of developing acute leukemia in Sudanese, however, the influence cannot be ruled out, so further study with a larger sample size is recommended. 

Keywords: Glutathione-S-transferase M1; Polymorphism; Acute Leukemia, Sudan

References

1. Clinical Diagnosis and Management. State University of New York Health Science. 16^th edition, Philadelphia, London-Toronto, Montreal Sydney and Tokyo (1991).
2. Jemal A., et al. "Cancer statistics, 2002". A Cancer Journal for Clinicians 52.1 (2002): 23-47.
3. Hoffman and Ronald. “Hematology: Basic Principles and Practice (4^th edition)”. St. Louis, Mo.: Elsevier Churchill Livingstone (2005): 1074-1075.
4. Boyle P and B Levin. “World cancer report 2008”. IARC Press, International Agency for Research on Cancer, Lyon, France (2008).
5. Ferlay J., et al. GLOBOCAN 2012 v1.0. Cancer Incidence Mortality Worldwide 2014 (2012).
6. Group WB. World Development Indicators 2012: World Bank Publications, Washington, DC, USA (2012).
7. Saeed IE., et al. “Cancer incidence in Khartoum, Sudan: first results from the Cancer Registry, 2009-2010”. Cancer Medicine 3.4 (2014): 1075-1085.
8. Ali AA and Ibrahim FE. “Incidence and geographical distribution of cancer in Radiation and Isotopes Center in Khartoum”. Sudan Medical Monitor 9 (2014): 109-112.
9. Hayes JD and Pulford DJ. “The glutathione S-transferase supergene family: regulation or GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance”. Critical Reviews in Biochemistry and Molecular Biology 309.6 (1995): 445-600. 
10. Strange RC., et al. “Glutathione-Stransferase family of enzymes”. Mutation Research 482.1-2 (2001): 21-26.
11. Seidegard J., et al. “Hereditary difference in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion”. Proceedings of the National Academy of Sciences of the United States of America 85.19 (1988): 7293-7297.
12. Bell DA., et al. “Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1(GSTM1) that increase susceptibility to bladder cancer”. Journal of the National Cancer Institute 85 (1993): 1159-1164.
13. Katoh T., et al. “Cytochrome P4501A1 gene polymorphism and homozygous deletion of the glutathione S-transferase M1 gene in urothelial cancer patients”. Carcinogenesis 16 (1995): 655-657.
14. Nelson HN., et al. “Ethnic differences in the prevalence of the homozygous deleted genotype of glutathione S-transferase theta”. Carcinogenesis 16 (1995): 1243-1245.
15. Chenevix-Trench G., et al. “Glutathione S-transferase M1 and T1 polymorphisms: susceptibility to colon cancer and age of onset”. Carcinogenesis 16 (1995): 1655-1657.
16. Zhong S., et al. “Glutathione S-transferase mu locus: use of genotyping and phenotyping assays to asses association with lung cancer susceptibility”. Carcinogenesis 12 (1991): 1533-1537. 
17. Bruhn C., et al. “Concordance between enzyme activity and genotype of glutathione S-transferase theta (GST T1)”. Biochemical Pharmacology 56 (1998): 1189-1193.
18. Chen CL., et al. “Higher frequency of glutathione S-transferase deletions in black children with acute lymphoblastic leukemia”. Blood 89.5 (1997): 1701-1707.
19. Souza CL., et al. “Polymorphisms in the glutathione S-transferase theta and mu genes and susceptibility to myeloid leukemia in Brazilian patients”. Genetics and Molecular Biology 31.1 (2008): 39-41.
20. Törüner GA., et al. “Polymorphisms of glutathione S-transferase genes (GSTM1, GSTP1 and GSTT1) and bladder cancer susceptibility in the Turkish population”. Archives of Toxicology 75.8 (2001): 459-464.
21. Joseph T., et al. “Genetic polymorphism of CYP1A1, CYP2D6, GSTM1 and GSTT1 and susceptibility to acute lymphoblastic leukaemia in Indian children”. Pediatric Blood and Cancer 43.5 (2004): 560-567.
22. Al-Eitan LN., et al. “GSTM1 and GSTP1 Genetic Polymorphisms and their Associations with Acute Lymphoblastic Leukemia Susceptibility in a Jordanian Population”. Journal of Pediatric Hematology/Oncology 38.7 (2016): e223-229.
23. Arruda VR., et al. “Increased risk of acute myeloid leukemia in individuals with glutathione S-transferase mu 1 (GSSTM1) and theta 1 (GSST1) gene defects”. European Journal of Hematology 66.6 (2001): 383-388.
24. Moawia S., et al. “Glutathione S-transferase T1, M1 genetic polymorphisms in cases of acute leukemia”. Journal of Clinical Oncology 25.90180 (2007): 7053.
25. Ali M., et al. “Deletion Polymorphism of Glutathione S-transferases M1 and T1 genes in the Sudanese Population”. American Journal of Medicine Studies 3.1 (2015): 8-12.
26. Taha MA. “Polymorphisms in Glutathione S-Transferees (GST) M1 and STransferees (GST) T1 Genes in Sudanese Patients with Myeloid Leukemia”. (Doctoral dissertation, Sudan University of Science & Technology).
27. Altaye b SM., et al. “GSTT1 Polymorphism in sudanese patients with polycythaemia vera”.
28. Omer RE., et al. “Peanut butter intake, GSTM1 genotype and hepatocellular carcinoma: a case-control study in Sudan”. Cancer Causes and Control 12.1 (2001): 23-32. 
29. A Zehra. “Glutathione S-Transferase M1 and T1 Gene Deletions and Susceptibility to Acute Lymphoblastic Leukemia (ALL) in adults”. Pakistan Journal of Medical Sciences 34.3 (2018): 666-670. 
30. G Castelli. “Emerging role of EPHX1 in chemoresistance of acute myeloid leukemia by regulating drug-metabolizing enzymes and apoptotic signaling”. Molecular Carcinogenesis 58.5 (2019): 808-819.