Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia

Br J Clin Pharmacol. 2019 Jul;85(7):1585-1597. doi: 10.1111/bcp.13943. Epub 2019 May 27.

Abstract

Aims: We aimed to investigate the impact of various genetic polymorphisms affecting thiopurine metabolism pathways and toxicity in paediatric acute lymphoblastic leukaemia patients for the first time in Korea.

Methods: From May 2006 to September 2016, 139 paediatric acute lymphoblastic leukaemia patients treated with combination chemotherapy including 6-mercaptopurine were included in the study. One hundred and twenty-three variants in 43 genes, including TMPT and NUDT15, were screened using targeted genotyping, such as a MassARRAY system, direct sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Among the polymorphisms screened, 103 polymorphisms of 43 genes were included for further analyses.

Results: The genetic polymorphisms in the ABCC4, AHCY, ATIC, FAM8A6P, GART, GNG2, GSTA1, MTHFD1, MTHFR, NUDT15, PACSIN2, TYMS and XDH genes, and an intronic polymorphism between HIVEP2 and AIG1, and TPMT genotype were associated with thiopurine metabolism (P < 0.05). Genetic polymorphisms in the ABCC4, ADK, ATIC, GART, GMPS, GSTP1, IMPDH1, ITPA, KCNMA1, MOCOS, MTRR, NUDT15, SLC19A1, SLC28A3, SLC29A1, SLCO1B1, TYMP and XDH genes were associated with thiopurine-related toxicities; neutropenia, hepatotoxicity and treatment interruption (P < 0.05).

Conclusions: Findings of this study may provide basic knowledge for personalized medicine for thiopurinxe treatment in paediatric acute lymphoblastic leukaemia patients.

Keywords: acute leukaemia; genome-wide association study; paediatric; polymorphisms; thiopurine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Child
  • Child, Preschool
  • Female
  • Genotype
  • Humans
  • Male
  • Mercaptopurine / administration & dosage
  • Polymerase Chain Reaction
  • Polymorphism, Restriction Fragment Length
  • Polymorphism, Single Nucleotide
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Republic of Korea
  • Retrospective Studies

Substances

  • Mercaptopurine