Genetic study of Thiopurin S-Methyltransferase and nudix hydrolase genes in a sample of Iraqi children


An essential anti-cancer drugs in Acute Lymphoblastic Leukemia treatment protocols since long time are Thiopurines. In addition, thiopurines are also used in the treatment of chronic inflammatory bowel diseases, autoimmune diseases and as immunosuppressant after organ transplantation. However, 6-Mercaptopurine can cause unexpected frequent toxicities in Acute Lymphoblastic Leukemia patients because of low activity of thiopurine S-methyltransferase. Thiopurine, intolerance is related to genetic polymorphism in Nudix hydrolase 15 and thiopurine S-methyltransferase. To measure the frequency of thiopurine S-methyltransferase and Nudix hydrolase 15 polymorphisms and assess whether they are predictors of 6-Mercaptopurine intolerance in Iraqi children treated for Acute Lymphoblastic Leukemia. Results showed that mutant paterns AG present in patients and controls, with genotypic frequency of (18%) in patients and (12%) in controls. Whereas, the homozygous mutant type (GG) for thiopurine S methyltransferase gene and homozygous and heterozygous mutant type (CT/TT) for Nudix hydrolase Nudix hydrolase 15 did not detected in patients and controls. Heterozygous mutant type (AG) of SNP 719A>G was significant in 6-Mercaptopurine resistant to Acute Lymphoblastic Leukemia patients as compared with patients don’t have resistant to 6-Mercaptopurine and showed good response in Acute Lymphoblastic Leukemia patients with P≤0.05. These explorative results lead to propose the prospect of exploration the SNPs 719A>G as biomarkers to predict the expected respons to 6-Mercaptopurine in Acute Lymphoblastic Leukemia patients before using 6-Mercaptopurine as a treatment.


  • Ahmed SJ, Ghali HH, Rasheed MK, Mohammed NS (2018) Detection of Thiopurine S-Methyltransferase (TPMT) Polymorphisms TPMT* 3A, TPMT* 3B and TPMT* 3C in Children with Acute Lymphoblastic Leukemia. Journal of the Faculty of Medicine, 60(3):166-71.
  • Albayrak M, Konyssova U, Kaya Z, Gursel T, Guntekin S, Percin EF, Kocak U (2011 Nov 1) Thiopurine methyltransferase polymorphisms and mercaptopurine tolerance in Turkish children with acute lymphoblastic leukemia. Cancer chemotherapy and pharmacology, 68(5):1155-9.
  • Alrudainy LA, Hassan JG, Salih HM, Abbas MK, Majeed AA (2011 May) Time trends and geographical distribution of childhood leukaemia in basrah, iraq, from 2004 to 2009. Sultan Qaboos Univ Medical Journal, 11(2):215-220.
  • Alsous M, Yousef AM, Jalil MA, Zawiah M, Yacoub S, et al. (2018) Genetic Polymorphism of Thiopurine S-methyltransferase in Children with Acute Lymphoblastic Leukemia in Jordan. Asian Pacific journal of cancer prevention: APJCP, 19(1): 199-205.
  • Chiengthong K, Ittiwut C, Muensri S, Sophonphan J, et al. (2016 Jan) NUDT15 c. 415C> T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica, 101(1):e24-6.
  • Cooper S L,and Brown PA. Treatment of pediatric acute lymphoblastic leukemia. Pediatric Clinics, 62(1),pp.61-73.
  • Delaneau O, Zagury JF, Marchini J (2013 Jan) Improved whole-chromosome phasing for disease and population genetic studies. Nature methods, 10(1): 5-6.
  • Goldstein DB, Ahmadi KR, Weale ME, Wood NW (2003 Nov 1) Genome scans and candidate gene approaches in the study of common diseases and variable drug responses. Trends in Genetics, 19(11): 615-22.
  • Gurney H, Wong M, Balleine RL, Rivory LP, McLachlan AJ, et al. (2007 Jul) Imatinib disposition and ABCB1 (MDR1, P‐Glycoprotein) genotype. Clinical Pharmacology & Therapeutics, 82(1): 33-40.
  • Hamidovic A, Hahn K, Kolesar J (2010 Mar) Clinical significance of ABCB1 genotyping in oncology. Journal of Oncology Pharmacy Practice, 16(1):39-44.
  • Jamieson C, Karimi M, Creusot R, Negrin R, Gotlib J, et al. (2005) Bioluminescent Imaging of Human Leukemic Stem Cell Engraftment: 696-696.
  • Jarrar YB, Ghishan M (2019) The Nudix Hydrolase 15 (NUDT15) Gene Variants among Jordanian Arab Population. Asian Pacific journal of cancer prevention: APJCP, 20(3): 801-808.
  • Karran P, Attard N (2008 Jan) Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nature Reviews Cancer, 8(1):24-36.
  • Kassaw E, Yohannes T, Bizualem E (2018) In-Vitro Antibacterial Activity of Plantago Lanceolata Against Some Selected Standard Pathogenic Bacterial. The International Journal of Biotechnology, 7(1): 44-50.
  • Landier W, Chen Y, Hageman L, Kim H, Bostrom BC, et al. (2017 Apr 6) Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children’s Oncology Group study. Blood, The Journal of the American Society of Hematology, 129(14):1919-1926.
  • Liang DC, Yang CP, Liu HC, Jaing TH, Chen SH, et al. (2016 Nov) NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. The pharmacogenomics journal, 16(6):536-9.
  • Lund B, Åsberg A, Heyman M, Kanerva J, Harila‐Saari A, et al. (2011 Apr) Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. Pediatric blood & cancer, 56(4): 551-9.
  • Maagdenberg H, Vijverberg SJ, Bierings MB, Carleton BC, et al. (2016 Aug 1) Pharmacogenomics in pediatric patients: towards personalized medicine. Pediatric Drugs, 18(4):251-60.
  • McLeod HL, Miller DR, Evans WE (1993 May 1) Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. The Lancet, 341(8853): 1151.
  • Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, et al. (2016 Apr) NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nature genetics, 48(4):367-73.
  • Pui CH, Mullighan CG, Evans WE, Relling MV (2012 Aug 9) Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?. Blood, The Journal of the American Society of Hematology, 120(6): 1165-74.
  • Schütz E, Gummert J, Mohr F, Oellerich M (1993 Feb 13) Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. The Lancet, 341(8842): 436.
  • Shu WY, Li JL, Wang XD, Huang M (2015 May) Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population. Acta pharmacologica Sinica, 36(5): 535-43.
  • Yang JJ, Landier W, Yang W, Liu C, Hageman L, et al. (2015 Apr 10) Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. Journal of clinical oncology, 33(11): 1235-1242.
  • Zeglam HB, Benhamer A, Aboud A, Rtemi H, Mattardi M, Saleh SS, et al. (2015) Polymorphisms of the thiopurine S-methyltransferase gene among the Libyan population. Libyan Journal of Medicine, 10: 27053-10.
  • Zgheib NK, Akika R, Mahfouz R, Aridi CA, Ghanem KM, et al. (2017 Jan) NUDT15 and TPMT genetic polymorphisms are related to 6‐mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children’s Cancer Center of Lebanon. Pediatric blood & cancer, 64(1):146-50.
  • Zhou H, Li L, Yang P, Yang L, Zheng JE, Zhou Y, Han Y (2018 Dec) Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?. BMC cancer, 18(1):516-525.


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