Medical Oncology

, Volume 27, Issue 4, pp 1046–1049 | Cite as

Frequency of TPMT alleles in Indian patients with acute lymphatic leukemia and effect on the dose of 6-mercaptopurine

  • Salamun Desire
  • Poonkuzhali Balasubramanian
  • Ashish Bajel
  • Biju George
  • Auro Viswabandya
  • Vikram Mathews
  • Alok Srivastava
  • Mammen ChandyEmail author
Original paper


Functional polymorphisms in the thiopurine methyl transferase (TPMT) gene have been associated with varying levels of enzyme activity and the occurrence of toxicity related to thiopurines. A total of 98 patients (66 pediatric and 32 adults) with precursor B acute lymphoblastic leukemia (Pre-B ALL) were evaluated for TPMT gene polymorphisms. The inability to tolerate 6-mercaptopurine (6-MP) at conventional doses was considered as a surrogate marker of hematologic toxicity. The allele frequency of TPMT*2, *3A, *3B and *3C in the study population was 0.5, 0, 0 and 2.6%, respectively, similar to the frequency observed in other Asian populations. Five patients were heterozygous for TPMT*3C variant allele, and one of these patient’s was compound heterozygous with TPMT*2 variant as the other allele. The impact of TPMT polymorphisms on the toxicity and treatment outcome was assessed in 66 pediatric patients only, as there was no variant TPMT detected in the adult patients. Three of the 5 patients (60%) heterozygous for TPMT*2 or TPMT*3C polymorphisms and 12/61 patients (20%) with wild type TPMT genotype had more than 10% of reduction of 6-MP dose (P = 0.07). The presence of TPMT polymorphisms did not seem to completely explain the variation in 6-MP toxicity in this small group of patients. Other novel variants in TPMT or variations in the genes involved in transport and biotransformation of 6-MP need to be evaluated in the Indian population.


TPMT Polymorphism 6-Mercaptopurine Acute lymphoblastic leukemia 


  1. 1.
    Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980;32(5):651–62.PubMedGoogle Scholar
  2. 2.
    Krynetski EY, Tai HL, Yates CR, et al. Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics. 1996;6(4):279–90.PubMedCrossRefGoogle Scholar
  3. 3.
    McLeod HL, Pritchard SC, Githang’a J, et al. Ethnic differences in thiopurine methyltransferase pharmacogenetics: evidence for allele specificity in Caucasian and Kenyan individuals. Pharmacogenetics. 1999;9(6):773–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Tai HL, Krynetski EY, Yates CR, et al. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet. 1996;58(4):694–702.PubMedGoogle Scholar
  5. 5.
    Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997;126(8):608–14.PubMedGoogle Scholar
  6. 6.
    Otterness DM, Szumlanski CL, Wood TC, Weinshilboum RM. Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity. J Clin Invest. 1998;101(5):1036–44.PubMedCrossRefGoogle Scholar
  7. 7.
    Otterness D, Szumlanski C, Lennard L, et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther. 1997;62(1):60–73.PubMedCrossRefGoogle Scholar
  8. 8.
    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(4):567–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Corominas H, Baiget M. Clinical utility of thiopurine S-methyltransferase genotyping. Am J Pharmacogenomics. 2004;4(1):1–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Relling MV, Hancock ML, Rivera GK, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999;91(23):2001–8.PubMedCrossRefGoogle Scholar
  11. 11.
    McLeod HL, Relling MV, Liu Q, et al. Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood. 1995;85(7):1897–902.PubMedGoogle Scholar
  12. 12.
    Brenner TL, Pui CH, Evan WE. Pharmacogenomics of childhood acute lymphoblastic leukemia. Curr Opin Mol Ther. 2001;3(6):567–78.PubMedGoogle Scholar
  13. 13.
    McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus—implications for clinical pharmacogenomics. Pharmacogenomics. 2002;3(1):89–98.PubMedCrossRefGoogle Scholar
  14. 14.
    Bajel A, George B, Mathews V, et al. Treatment of children with acute lymphoblastic leukemia in India using a BFM protocol. Pediatr Blood Cancer. 2008;51(5):621–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Bajel A, George B, Mathews V, et al. Adult ALL: treatment outcome and prognostic factors in an Indian population using a modified German ALL (GMALL) protocol. Leukemia. 2007;21(10):2230–3.PubMedCrossRefGoogle Scholar
  16. 16.
    Stanulla M, Schaeffeler E, Moricke A, et al. Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Munster protocols. Blood. 2009;114(7):1314–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Kham SK, Tan PL, Tay AH, et al. Thiopurine methyltransferase polymorphisms in a multiracial asian population and children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2002;24(5):353–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Ameyaw MM, Collie-Duguid ES, Powrie RH, et al. Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet. 1999;8(2):367–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Kham SK, Soh CK, Liu TC, et al. Thiopurine S-methyltransferase activity in three major Asian populations: a population-based study in Singapore. Eur J Clin Pharmacol. 2008;64(4):373–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Collie-Duguid ES, Pritchard SC, Powrie RH, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics. 1999;9(1):37–42.PubMedCrossRefGoogle Scholar
  21. 21.
    Schaeffeler E, Fischer C, Brockmeier D, et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics. 2004;14(7):407–17.PubMedCrossRefGoogle Scholar
  22. 22.
    Ganiere-Monteil C, Medard Y, Lejus C, et al. Phenotype and genotype for thiopurine methyltransferase activity in the French Caucasian population: impact of age. Eur J Clin Pharmacol. 2004;60(2):89–96.PubMedCrossRefGoogle Scholar
  23. 23.
    Boson WL, Romano-Silva MA, Correa H, et al. Thiopurine methyltransferase polymorphisms in a Brazilian population. Pharmacogenomics J. 2003;3(3):178–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Evans WE, Hon YY, Bomgaars L, et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol. 2001;19(8):2293–301.PubMedGoogle Scholar
  25. 25.
    McLeod HL, Coulthard S, Thomas AE, et al. Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol. 1999;105(3):696–700.PubMedCrossRefGoogle Scholar
  26. 26.
    Spire-Vayron de la Moureyre C, Debuysere H, Mastain B, et al. Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population. Br J Pharmacol. 1998;125(4):879–87.PubMedCrossRefGoogle Scholar
  27. 27.
    Stanulla M, Schaeffeler E, Flohr T, et al. Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. Jama. 2005;293(12):1485–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Ma XL, Zhu P, Wu MY, et al. Relationship between single nucleotide polymorphisms in thiopurine methyltransferase gene and tolerance to thiopurines in acute leukemia. Zhonghua Er Ke Za Zhi. 2003;41(12):929–33.PubMedGoogle Scholar
  29. 29.
    Hongeng S, Sasanakul W, Chuansumrit A, et al. Frequency of thiopurine S-methyltransferase genetic variation in Thai children with acute leukemia. Med Pediatr Oncol. 2000;35(4):410–4.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Salamun Desire
    • 1
  • Poonkuzhali Balasubramanian
    • 1
  • Ashish Bajel
    • 1
  • Biju George
    • 1
  • Auro Viswabandya
    • 1
  • Vikram Mathews
    • 1
  • Alok Srivastava
    • 1
  • Mammen Chandy
    • 1
    Email author
  1. 1.Department of HaematologyChristian Medical CollegeVelloreIndia

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