Advertisement

Prevalence of TPMT, ITPA and NUDT 15 genetic polymorphisms and their relation to 6MP toxicity in north Indian children with acute lymphoblastic leukemia

  • Sanjeev Khera
  • Amita Trehan
  • Prateek Bhatia
  • Minu Singh
  • Deepak Bansal
  • Neelam Varma
Original Article
  • 75 Downloads

Abstract

Purpose

Toxicity of 6-Mercaptopurine (6MP) is related to single nucleotide polymorphism (SNP) in genes coding for metabolizing enzymes, with TPMT analysis being recommended prior to maintenance therapy. However, ITPA and NUDT15 polymorphisms appear more important in the Asian population.

Method

In this study 63 consecutive patients with ALL, entering maintenance phase of therapy, were evaluated for TPMT, ITPA and NUDT15 polymorphisms by PCR RFLP and confirmed by sequencing. Hematological and hepatic toxicities were monitored for 36 weeks. The groups with and without any of the three studied polymorphisms (Risk SNP + and Risk SNP-) were compared.

Results

Eighteen (28.6%) patients had major polymorphisms, 17 being heterozygous. ITPA(198CA): 11(17.5%); NUDT (415CT): 6(9.5%) and TPMT*3C: in 2(3.1%). Mean cumulative dose of 6MP was lower: 10927 mg/m2 in group with one of the polymorphisms compared to 12533 mg/m2 in the group without a polymorphism (p = 0.009). The group with Risk SNP + tolerated lesser weeks of full-dose 6MP chemotherapy (20.81 vs 30.40 weeks; p = 0.001). Risk of neutropenia > 3 weeks was pronounced in Risk SNP + group. The individual TPMT, ITPA and NUDT15 polymorphism subgroups had similar cumulative 6MP dose and chemotherapy interruptions. There was no difference in the average cumulative dose of methotrexate in the two groups. No significant hepatotoxicity was noted.

Conclusion

Polymorphisms in ITPA and NUDT15 have a greater prevalence in the north Indian population. Patients with these SNPs tolerate lower doses of 6MP.

Keywords

ALL 6 Mercaptopurine Single neucleotide polymorphism Myelosuppression Drug dose 

Abbreviations

6 MP

6-Mercaptopurine

SNP

Single nucleotide polymorphism

ALL

Acute lymphoblastic leukaemia

TPMT

Thiopurine methyltransferase

ITPA

Inosine triphosphate pyrophosphatase

NUDT15

Nucleoside diphosphate linked moiety-type motif 15

ICICLE

Indian Childhood Collaborative Leukaemia Group 2015

MTX

Methotrexate

PCR-RFLP

PCR amplification and restriction enzyme digestion

ALT

Alanine transferase

FN

Febrile neutropenia

ANC

Absolute neutrophil count

HWE

Hardy Weinberg equilibrium

ANOVA

Analysis of variance

6TGN

6-Thioguanine

TLC

Total leucocyte count

CBC

Complete blood count

PCR

Polymerized chain reaction

Notes

Compliance ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

280_2018_3732_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 12 KB)
280_2018_3732_MOESM2_ESM.docx (12 kb)
Supplementary material 2 (DOCX 12 KB)
280_2018_3732_MOESM3_ESM.docx (15 kb)
Supplementary material 3 (DOCX 14 KB)

References

  1. 1.
    Wall AM, Rubnitz JE (2003) Pharmacogenomic effects on therapy for acute lymphoblastic leukemia in children. Pharmacogenomics J, 3:128CrossRefGoogle Scholar
  2. 2.
    Evans WE et al (2001) Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 19(8):2293–2301CrossRefGoogle Scholar
  3. 3.
    Moriyama T, Relling MV, Yang JJ (2015) Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood 125(26):3988–3995CrossRefGoogle Scholar
  4. 4.
    Relling MV et al (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91(23):2001–2008CrossRefGoogle Scholar
  5. 5.
    Relling MV et al (2013) Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin Pharmacol Ther 93(4):324–325CrossRefGoogle Scholar
  6. 6.
    Chang JG et al (2002) Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics 12(3):191–195CrossRefGoogle Scholar
  7. 7.
    Srimartpirom S et al (2004) Thiopurine S-methyltransferase genetic polymorphism in the Thai population. Br J Clin Pharmacol 58(1):66–70CrossRefGoogle Scholar
  8. 8.
    Tanaka Y et al (2012) The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children. Leuk Res 36(5):560–564CrossRefGoogle Scholar
  9. 9.
    Yang SK et al (2014) A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 46(9):1017–1020CrossRefGoogle Scholar
  10. 10.
    Chiengthong K et al (2016) NUDT15 c.415C> T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica 101(1):e24–e26CrossRefGoogle Scholar
  11. 11.
    Yates CR et al. (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 126:608–614CrossRefGoogle Scholar
  12. 12.
    Cao H, Hegele RA (2002) DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency. J Hum Genet 47:620CrossRefGoogle Scholar
  13. 13.
    Schmiegelow K et al (2014) Mercaptopurine/methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol 36(7):503–517CrossRefGoogle Scholar
  14. 14.
    Kapoor G et al. (2010) Thiopurine S-methyltransferase gene polymorphism and 6-mercaptopurine dose intensity in Indian children with acute lymphoblastic leukemia. Leuk Res 34:1023–1026CrossRefGoogle Scholar
  15. 15.
    Davavala SK et al (2014) Prevalence of TPMT polymorphism in Indian patients requiring immunomodulator therapy and its clinical significance. Indian J Gastroenterol 33(1):41–45CrossRefGoogle Scholar
  16. 16.
    Desire S et al (2010) Frequency of TPMT alleles in Indian patients with acute lymphatic leukemia and effect on the dose of 6-mercaptopurine. Med Oncol 27(4):1046–1049CrossRefGoogle Scholar
  17. 17.
    Soler AM et al. (2017) TPMT and NUDT15 genes are both related to mercaptopurine intolerance in acute lymphoblastic leukaemia patients from Uruguay. Br J Haematol 181:252–255CrossRefGoogle Scholar
  18. 18.
    Wan Rosalina WR et al (2012) Polymorphism of ITPA 94C> A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine. J Clin Pharm Ther 37(2):237–241CrossRefGoogle Scholar
  19. 19.
    Kim HT et al (2017) NUDT15 genotype distributions in the Korean population. Pharmacogenet Genom 27(5):197–200CrossRefGoogle Scholar
  20. 20.
    Schmiegelow K, Bruunshuus I (1990) 6-Thioguanine nucleotide accumulation in red blood cells during maintenance chemotherapy for childhood acute lymphoblastic leukemia, and its relation to leukopenia. Cancer Chemother Pharmacol 26(4):288–292CrossRefGoogle Scholar
  21. 21.
    Yang JJ et al (2015) Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol 33(11):1235–1242CrossRefGoogle Scholar
  22. 22.
    Farfan MJ et al (2014) Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia. BMC Cancer 14(1):299CrossRefGoogle Scholar
  23. 23.
    Ma X et al (2014) Inosine triphosphate pyrophosphohydrolase (ITPA) polymorphic sequence variants in Chinese ALL children and possible association with mercaptopurine related toxicity. Int J Clin Exp Pathol 7(7):4552–4556PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pediatric Hematology and Oncology, Department of Pediatrics, Advanced Pediatrics CentrePostgraduate Institute of Medical Education and ResearchChandigarhIndia
  2. 2.Department of HematologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia

Personalised recommendations