Clinical implication of thiopurine methyltransferase polymorphism in children with acute lymphoblastic leukemia: A preliminary Egyptian studyFinancial support and sponsorship Nil.
Background: 6-mercaptopurine (6-MP) is an essential component of pediatric acute lymphoblastic leukemia (ALL) maintenance therapy. Individual variability in this drug-related toxicity could be attributed in part to genetic polymorphism thiopurine methyltransferase (TPMT). Aim: To investigate the frequency of common TPMT polymorphisms in a cohort of Egyptian children with ALL and the possible relation between these polymorphisms and 6-MP with short-term complications. Materials and Methods: This study included 25 children. Data related to 6-MP toxicity during the maintenance phase were collected from the patients′ files. DNA was isolated and genotyping for TPMT G460A, and A719G mutations were performed by polymerase chain reaction-restriction fragment length polymorphism. Results: Twenty (80%) of the included 25 patients had a polymorphic TPMT allele. TPMTFNx013A was the most frequent (14/25, 56%), 8 patients were homozygous and 6 were heterozygous. TPMTFNx013C mutant allele was found in 4 patients (16%) in the heterozygous state while 2 patients (8%) were found to be heterozygous for TPMTFNx013B mutant allele. TPMT mutant patients, especially homozygous, were at greater risk of 6-MP hematological toxicity without significant difference regarding hepatic toxicity. Conclusions: TPMT polymorphism was common among the studied group and was associated with increased risk of drug toxicity. A population-based multi-center study is required to confirm our results.
Keywords6-mercaptopurine - acute lymphoblastic leukemia - pharmacogenetic - polymorphism - thiopurine methyltransferase
12. Juli 2021 (online)
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- 1 Rubnitz JE, Pui CH. Recent advances in the treatment and understanding of childhood acute lymphoblastic leukaemia. Cancer Treat Rev 2003;29:31-44.
- 2 Schmiegelow K, Schrøder H, Gustafsson G, Kristinsson J, Glomstein A, Salmi T, et al. Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology. J Clin Oncol 1995;13:345-51.
- 3 Chessells JM, Harrison G, Lilleyman JS, Bailey CC, Richards SM. Continuing (maintenance) therapy in lymphoblastic leukaemia: Lessons from MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia. Br J Haematol 1997;98:945-51.
- 4 Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 1998;338:499-505.
- 5 Pieters R, Carroll WL. Biology and treatment of acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2010;24:1-18.
- 6 Lennard L, Maddocks JL. Assay of 6-thioguanine nucleotide, a major metabolite of azathioprine, 6-mercaptopurine and 6-thioguanine, in human red blood cells. J Pharm Pharmacol 1983;35:15-8.
- 7 Adam de Beaumais T, Jacqz-Aigrain E. Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia. Eur J Clin Pharmacol 2012;68:1233-42.
- 8 Krynetski EY, Tai HL, Yates CR, Fessing MY, Loennechen T, Schuetz JD, et al. Genetic polymorphism of thiopurine S-methyltransferase: Clinical importance and molecular mechanisms. Pharmacogenetics 1996;6:279-90.
- 9 Chrzanowska M, Kuehn M, Januszkiewicz-Lewandowska D, Kurzawski M, Drozdzik M. Thiopurine S-methyltransferase phenotype-genotype correlation in children with acute lymphoblastic leukemia. Acta Pol Pharm 2012;69:405-10.
- 10 Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 1999;91:2001-8.
- 11 Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R, et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 2001;19:2293-301.
- 12 Ujiie S, Sasaki T, Mizugaki M, Ishikawa M, Hiratsuka M. Functional characterization of 23 allelic variants of thiopurine S-methyltransferase gene (TPMTFNx012 - FNx0124). Pharmacogenet Genomics 2008;18:887-93.
- 13 Rutherford K, Daggett V. Four human thiopurine s-methyltransferase alleles severely affect protein structure and dynamics. J Mol Biol 2008;379:803-14.
- 14 Evans WE. Comprehensive assessment of thiopurine S-methyltransferase (TPMT) alleles in three ethnic populations. J Pediatr Hematol Oncol 2002;24:335-6.
- 15 Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89:387-91.
- 16 Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009;360:2730-41.
- 17 Peregud-Pogorzelski J, Tetera-Rudnicka E, Kurzawski M, Brodkiewicz A, Adrianowska N, Mlynarski W, et al. 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;57:578-82.
- 18 National Cancer Institute. Common Terminology Criteria for Adverse Events, version 2.0 (CTCAE). Published April 30, 1999. Available from: http://www.ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf [Last accessed on 2015 May 12].
- 19 Serpe L, Calvo PL, Muntoni E, D′Antico S, Giaccone M, Avagnina A, et al. Thiopurine S-methyltransferase pharmacogenetics in a large-scale healthy Italian-Caucasian population: Differences in enzyme activity. Pharmacogenomics 2009;10:1753-65.
- 20 Sirchia G, Pizzi C, Scalamogna M. A simple procedure for human lymphocyte isolation from peripheral blood. Tissue Antigens 1972;2:139-40.
- 21 Chowdhury J, Kagiala GV, Pushpakom S, Lauzon J, Makin A, Atrazhev A, et al. Microfluidic platform for single nucleotide polymorphism genotyping of the thiopurine S-methyltransferase gene to evaluate risk for adverse drug events. J Mol Diagn 2007;9:521-9.
- 22 Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 1999;286:487-91.
- 23 Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum Mol Genet 1999;8:371-6.
- 24 McLeod HL, Pritchard SC, Githang′a J, Indalo A, Ameyaw MM, Powrie RH, et al. Ethnic differences in thiopurine methyltransferase pharmacogenetics: Evidence for allele specificity in Caucasian and Kenyan individuals. Pharmacogenetics 1999;9:773-6.
- 25 Hiratsuka M, Inoue T, Omori F, Agatsuma Y, Mizugaki M. Genetic analysis of thiopurine methyltransferase polymorphism in a Japanese population. Mutat Res 2000;448:91-5.
- 26 Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 1999;9:37-42.
- 27 Ayesh BM, Harb WM, Abed AA. Thiopurine methyltransferase genotyping in Palestinian childhood acute lymphoblastic leukemia patients. BMC Hematol 2013;13:3.
- 28 Melaouhia S, Fékih M, Garat A, Allorge D, Ferchichi H, Klouz A, et al. Allele frequency of inosine triphosphate pyrophosphatase (ITPA) and thiopurine-S-methyl transferase (TPMT) genes in the Tunisian population. Clin Res Hepatol Gastroenterol 2012;36:178-84.
- 29 Hamdy SI, Hiratsuka M, Narahara K, Endo N, El-Enany M, Moursi N, et al. Genotype and allele frequencies of TPMT, NAT2, GST, SULT1A1 and MDR-1 in the Egyptian population. Br J Clin Pharmacol 2003;55:560-9.
- 30 Aboul Naga SA, Ebid GT, Fahmi HM, Zamzam MF, Mahmoud S, Hafez HF, et al. Effects of thiopurine S-methyltransferase genetic polymorphism on mercaptopurine therapy in pediatric ALL. J Am Sci 2011;7:337-46.
- 31 El-Kaffash DM, Hassab HM, Abouzeid AA, Swelem RS, Tahoun MM. TPMT gene polymorphism detection by conventional PCR in pediatric acute lymphoblastic leukemia and its toxic effect. Egypt J Haematol 2014;39:86-90.
- 32 Farfan MJ, Salas C, Canales C, Silva F, Villarroel M, Kopp K, et al. Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia. BMC Cancer 2014;14:299.
- 33 Albayrak M, Konyssova U, Kaya Z, Gursel T, Guntekin S, Percin EF, et al. Thiopurine methyltransferase polymorphisms and mercaptopurine tolerance in Turkish children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2011;68:1155-9.
- 34 Desire S, Balasubramanian P, Bajel A, George B, Viswabandya A, Mathews V, et al. Frequency of TPMT alleles in Indian patients with acute lymphatic leukemia and effect on the dose of 6-mercaptopurine. Med Oncol 2010;27:1046-9.
- 35 Wall AM, Rubnitz JE. Pharmacogenomic effects on therapy for acute lymphoblastic leukemia in children. Pharmacogenomics J 2003;3:128-35.
- 36 McLeod HL, Krynetski EY, Relling MV, Evans WE. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 2000;14:567-72.
- 37 Relling MV, Pui CH, Cheng C, Evans WE. Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood 2006;107:843-4.
- 38 Dokmanovic L, Urosevic J, Janic D, Jovanovic N, Petrucev B, Tosic N, et al. Analysis of thiopurine S-methyltransferase polymorphism in the population of Serbia and Montenegro and mercaptopurine therapy tolerance in childhood acute lymphoblastic leukemia. Ther Drug Monit 2006;28:800-6.
- 39 McLeod HL, Coulthard S, Thomas AE, Pritchard SC, King DJ, Richards SM, et al. Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol 1999;105:696-700.
- 40 Silva MR, de Oliveira BM, Viana MB, Murao M, Romanha AJ. Thiopurine S-methyltransferase (TPMT) gene polymorphism in Brazilian children with acute lymphoblastic leukemia: Association with clinical and laboratory data. Ther Drug Monit 2008;30:700-4.
- 41 McLeod HL, Relling MV, Liu Q, Pui CH, Evans WE. Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood 1995;85:1897-902.
- 42 Stanulla M, Schaeffeler E, Flohr T, Cario G, Schrauder A, Zimmermann M, et al. Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA 2005;293:1485-9.