Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia

Authors

  • Jelena Lazić Department for hematology and oncology University Children`s Hospital, Belgrade, School of Medicine, University of Belgrade
  • Nikola Kotur Laboratory for Molecular Biomedicine, Institute of molecular genetics and genetic engineering, University of Belgrade, Belgrade, Serbia
  • Nada Krstovski Department for hematology and oncology University Children`s Hospital, Belgrade, School of Medicine, University of Belgrade
  • Lidija Dokmanović Department for hematology and oncology University Children`s Hospital, Belgrade, School of Medicine, University of Belgrade
  • Branka Zukić Laboratory for Molecular Biomedicine, Institute of molecular genetics and genetic engineering, University of Belgrade, Belgrade, Serbia
  • Jelica Predojević-Samardžić Children`s Hospital, University Clinic of Banja Luka, Republic of Srpska
  • Maja Životić Institute of pathology, School of Medicine, University of Belgrade, Serbia
  • Goran Miločević Department for hematology and oncology University Children`s Hospital, Belgrade
  • Milica Đorić School of Medicine, University of Belgrade
  • Dragana Janić Department for hematology and oncology University Children`s Hospital, Belgrade, School of Medicine, University of Belgrade
  • Sonja Pavlović Laboratory for Molecular Biomedicine, Institute of molecular genetics and genetic engineering, University of Belgrade, Belgrade, Serbia

Keywords:

pharmacogenetic markers, pediatric lymphoblastic leukemia, MTHFR c.677, MTHFR c.1298

Abstract

Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C>T and MTHFR c.1298A>C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCR-RFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C>T and MTHFR c.1298A>C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A>C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C>T and MTHFR c.1298A>C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C>T nor MTHFR c.1298A>C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy.

https://doi.org/10.2298/ABS160325091L

Received: March 25, 2016; Revised: April 12, 2016; Accepted: April 12, 2016; Published online: October 4, 2016

How to cite this article: Lazić J, Kotur N, Krstovski N, Dokmanović L, Zukić B, Predojević-Samardžić J, Životić M, Milošević G, Đorić M, Janić D, Pavlović S. Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia. Arch Biol Sci. 2017;69(2):239-46.

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Published

2017-05-25

How to Cite

1.
Lazić J, Kotur N, Krstovski N, Dokmanović L, Zukić B, Predojević-Samardžić J, Životić M, Miločević G, Đorić M, Janić D, Pavlović S. Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia. Arch Biol Sci [Internet]. 2017May25 [cited 2024Apr.19];69(2):239-46. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/268

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Vol. 69 No. 2 (2017)

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