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Influence of ADORA2A gene polymorphism on leukoencephalopathy risk in MTX-treated pediatric patients affected by

Shin-Ichi Tsujimoto1, Masakatsu Yanagimachi2, Reo Tanoshima1

  • 1Department of Pediatrics, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama City, Japan.

Pediatric Blood & Cancer
|July 12, 2016
PubMed
Abstract

Insights

Genetic variations in the adenosine pathway, specifically ADORA2A rs2298383, and high cumulative methotrexate doses are linked to MTX-related leukoencephalopathy in children. This suggests adenosine pathway interventions may prevent or treat this neurotoxicity.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Genetics

Background:

  • Methotrexate (MTX) is known to cause neurotoxicity and leukoencephalopathy, but the underlying mechanisms remain unclear.
  • MTX and its metabolites interfere with the 5-aminoimidazole-4-carboxamide ribonucleotide formiltransferase (ATIC) enzyme, leading to increased adenosine levels.
  • Adenosine and its receptors have been implicated in various central nervous system disorders.

Purpose of the Study:

  • To investigate the association between adenosine pathway gene polymorphisms and clinical factors with MTX-related leukoencephalopathy in pediatric patients with hematological malignancies.
  • To identify potential genetic and clinical risk factors for MTX-induced neurotoxicity.

Main Methods:

  • A cohort of 56 Japanese children with acute lymphoblastic leukemia or lymphoma was studied.
  • Brain MRIs were performed to assess leukoencephalopathy.
  • Genotyping for polymorphisms in adenosine pathway genes (ATIC, ADORA2A) and MTX pathway genes (MTHFR, ABCB1) was conducted.
  • Clinical data, including MTX dosage and concentration, were collected.

Main Results:

  • MTX-related leukoencephalopathy developed in 37% of patients (21 out of 56).
  • The CC genotype of ADORA2A rs2298383 (minor allele) was significantly associated with MTX-related leukoencephalopathy (OR=5.81, P=0.010).
  • High cumulative doses of systemic MTX were also independently associated with MTX-related leukoencephalopathy (OR=1.18, P=0.042).

Conclusions:

  • The ADORA2A rs2298383 polymorphism and high cumulative MTX doses are significant risk factors for MTX-related leukoencephalopathy.
  • Targeting the adenosine pathway pharmacologically could offer a potential strategy for preventing or treating MTX-induced neurotoxicity.
Keywords:
ADORA2Aadenosineleukoencephalopathymethotrexatepharmacogenetics

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