Thiopurine methyltransferase genotyping in Palestinian childhood acute lymphoblastic leukemia patients

BMC Hematology

Abdalla Assaf Abed¹  Wael Mohammad Harb³  Basim Mohammad Ayesh² 

[1] Biology Department, Islamic University of Gaza, Gaza, Palestinian authority;Medical Technology Department, Al Aqsa University, Gaza, Palestinian authority;MOH, Shouhada AL-Aqsa Hospital Laboratory, Gaza, Palestinian authority

关键词: Acute lymphoblastic leukemia;    TPMT;    Thiopurine S-methyltransferase;   

Others  :  865386
DOI  :  10.1186/2052-1839-13-3

 received in 2012-07-10, accepted in 2013-01-30,  发布年份 2013

【 摘 要 】

Background

The genetic polymorphism of thiopurine methyltransferase (TPMT) is well characterized in most populations. Four common polymorphic alleles are associated with impaired activity of the enzyme. These are TPMT*2 (238G>C), TPMT*3B (c.460G>A), TPMT*3A (c.460G>A and c.719A>G) and TPMT*3C (c.719A>G). The aim of the present study was to determine the frequency of TPMT polymorphisms and their association with the occurrence of adverse events, during 6-mercaptopurine therapy in pediatric acute lymphoblastic leukemic (ALL) patients in Gaza Strip.

Methods

A total of 56 DNA samples from all pediatric ALL patients admitted to the pediatric hematology departments of Gaza strip hospitals were analyzed. Genomic DNA from peripheral blood leukocytes was isolated and the TPMT*2, TPMT*3B TPMT*3A and TPMT*3C allelic polymorphism was determined by PCR-RFLP and allele specific PCR technique.

Results

No TPMT*2, *3B or *3C alleles were detected. Only one, out of 56 patients, was found heterozygous for the TPMT*3A allele. Thus, the frequency of TPMT*3A allele was calculated to be 0.89%. Fourteen patients of ALL were suffering from myelotoxicity during 6-MP therapy. From our results, no significant association could be established between clinical and laboratory data and/or the presence of the mutation in TPMT gene.

Conclusion

TPMT*3A was the only deficiency allele detected in our population with an allelic frequency of 0.89%. Other polymorphic alleles in TPMT gene, or factors other than TPMT polymorphisms may be responsible for the development of myelosuppression in cases that don’t carry the investigated TPMT alleles (*2, *3A, *3B and *3C). Therefore, more studies are recommended to study such factors.

【 授权许可】

   
2013 Ayesh et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Gale RP, Butturini A: Maintenance chemotherapy and cure of childhood acute lymphoblastic leukaemia. Lancet 1991, 338(8778):1315-1318.
• [2]Lennard L: The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 1992, 43(4):329-339.
• [3]Adam de Beaumais T, Jacqz-Aigrain E: Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia. Eur J Clin Pharmacol 2012, 68(9):1233-1242.
• [4]Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R, Kalwinsky D, Keller F, Khatib Z, Margolin J, Murray J, Quinn J, Ravindranath Y, Ritchey K, Roberts W, Rogers ZR, Schiff D, Steuber C, Tucci F, Kornegay N, Krynetski EY, Relling MV: Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 2001, 19(8):2293-2301.
• [5]Ujiie S, Sasaki T, Mizugaki M, Ishikawa M, Hiratsuka M: Functional characterization of 23 allelic variants of thiopurine S-methyltransferase gene (TPMT*2 - *24). Pharmacogenet Genomics 2008, 18(10):887-893.
• [6]Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, Relling MV, Evans WE: Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997, 126(8):608-614.
• [7]Krynetski EY, Tai HL, Yates CR, Fessing MY, Loennechen T, Schuetz JD, Relling MV, Evans WE: Genetic polymorphism of thiopurine methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 1996, 6(4):279-290.
• [8]McLeod HL, Lin JS, Scott EP, Pui C-H, Evans WE: Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 1994, 55(1):15-20.
• [9]Chrzanowska M, Kuehn M, Januszkiewicz-Lewandowska D, Kurzawski M, Droździk M: Thiopurine S-methyltransferase phenotype-genotype correlation in children with acute lymphoblastic leukemia. Acta Pol Pharm 2012, 69(3):405-410.
• [10]Szumlanski C, Otterness D, Her C, Lee D, Brandriff B, Kelsell D, Spurr N, Lennard L, Wieben E, Weinshilboum R: Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterisation of a common polymorphism. DNA Cell Biol 1996, 15(1):17-30.
• [11]World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. http://www.wma.net/en/30publications/10policies/b3/index.html webcite
• [12]Zhang JP, Guan Y, Wu JH, Xu AL, Zhou S, Huang M: Phenotyping and genotyping study of thiopurine S-methyltransferase in healthy Chinese children: A comparison of Han and Yao ethnic groups. Br J Clin Pharmacol 2004, 58(2):163-168.
• [13]Hindorf U, Appell ML: Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function. J Crohns Colitis 2012, 6(6):655-659.
• [14]Peregud-Pogorzelski J, Tetera-Rudnicka E, Kurzawski M, Brodkiewicz A, Adrianowska N, Mlynarski W, Januszkiewicz D, Drozdzik M: Thiopurine S-methyltransferase (TPMT) polymorphisms in children with acute lymphoblastic leukemia, and the need for reduction or cessation of 6-mercaptopurine doses during maintenance therapy: the Polish multicenter analysis. Pediatr Blood Cancer 2011, 57(4):578-582.
• [15]Higgs JE, Payne K, Roberts C, Newman WG: Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics 2010, 11(2):177-188.
• [16]Efrati E, Adler L, Krivoy N, Sprecher E: Distribution of TPMT risk alleles for thioupurine toxicity in the Israeli population. Eur J Clin Pharmacol 2009, 65(3):257-262.
• [17]Hakooz N, Arafat T, Payne D, Ollier W, Pushpakom S, Andrews J, Newman W: Genetic analysis of thiopurine methyltransferase polymorphism in the Jordanian population. Eur J Clin Pharmacol 2010, 66(10):999-1003.
• [18]Tumer TB, Ulusoy G, Adali O, Sahin G, Gozdasoglu S, Arinc E: The low frequency of defective TPMT alleles in Turkish population: a study on pediatric patients with acute lymphoblastic leukemia. Am J Hematol 2007, 82(10):906-910.
• [19]Azad M, Kaviani S, Soleimani M, Noruzinia M, Hajfathali A: Common Polymorphism’s Analysis of Thiopurine S-Methyltransferase (TPMT) in Iranian Population. Yakhteh Med J 2009, 11(3):311-316.
• [20]Marra C, Esdaile JM, Anis AH: Practical pharmacogenetics: The cost effectiveness of screening for thiopurine methyltransferase polymorphism in patients with rheumatological conditions treated with azathioprine. J Rheumatol 2002, 29(12):2507-2512.
• [21]Fakhoury M, Andreu-Gallien J, Mahr A, Medard Y, Azougagh S, Vilmer E, Jacqz-Aigrain E: Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment in children with acute lymphoblastic leukaemia? J Clin Pharm Ther 2007, 32(6):633-639.