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

Shin-Ichi Tsujimoto; Masakatsu Yanagimachi; Reo Tanoshima; Kevin Y Urayama; Fumiko Tanaka; Noriko Aida; Hiroaki Goto; Shuichi Ito

doi:10.1002/pbc.26090

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

Pediatr Blood Cancer. 2016 Nov;63(11):1983-9. doi: 10.1002/pbc.26090. Epub 2016 Jul 11.

Authors

Shin-Ichi Tsujimoto¹, Masakatsu Yanagimachi², Reo Tanoshima¹, Kevin Y Urayama³, Fumiko Tanaka⁴, Noriko Aida⁵, Hiroaki Goto⁶, Shuichi Ito¹

Affiliations

¹ Department of Pediatrics, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama City, Japan.
² Department of Pediatrics, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama City, Japan. myanagi@yokohama-cu.ac.jp.
³ Center for Clinical Epidemiology, St. Luke's International University, Chuo-ku, Tokyo, Japan.
⁴ Department of Pediatrics, Saiseikai Yokohama-Shi Nanbu Hospital, Kounan-ku, Yokohama City, Japan.
⁵ Department of Radiology, Kanagawa Children's Medical Center, Minami-ku, Yokohama City, Japan.
⁶ Department of Hematology and Oncology, Kanagawa Children's Medical Center, Minami-ku, Yokohama City, Japan.

PMID: 27399166
DOI: 10.1002/pbc.26090

Abstract

Background: Methotrexate (MTX) can lead to neurotoxicity and asymptomatic leukoencephalopathy. However, the mechanism of MTX-related leukoencephalopathy is obscure. MTX and its metabolites inhibit 5-aminoimidazole-4-carboxamide ribonucleotide formiltransferase (ATIC) and promote adenosine release. Recently, it has been reported that adenosine and its receptor are related to certain central nervous system diseases. We investigated whether adenosine pathway gene polymorphisms and clinical factors were related to MTX-related leukoencephalopathy in pediatric patients affected by hematological malignancies.

Procedure: Fifty-six Japanese childhood acute lymphoblastic leukemia or lymphoma patients were investigated. Patients were evaluated by magnetic resonance imaging of the brain before maintenance therapy or stem cell transplantation. Gene polymorphisms within the adenosine pathway (ATIC, adenosine A2A receptor [ADORA2A]) and the MTX pathway (methylenetetrahydrofolate reductase [MTHFR] and ABCB1) were genotyped using TaqMan assays. Clinical data were collected by accessing the medical records. MTX-related leukoencephalopathy was evaluated by a pediatric neurologist.

Results: Twenty-one (37%) of 56 patients developed MTX-related leukoencephalopathy. Four of 21 patients developed clinical neurotoxicity. The minor allele CC genotype of rs2298383 (ADORA2A) was associated with MTX-related leukoencephalopathy (P = 0.010, odds ratio = 5.81, 95% confidence interval 1.50-22.50). High cumulative dose of systemic MTX was associated with MTX-related leukoencephalopathy after adjusting for sex, ADORA2A polymorphism, and prolonged high MTX concentration (P = 0.042, odds ratio = 1.18, 95% confidence interval 1.01-1.37).

Conclusions: ADORA2A rs2298383 and high cumulative dose of systemic MTX administration were significantly associated with MTX-related leukoencephalopathy. Our results indicate that pharmacological intervention within the adenosine pathway may be both a treatment and preventative option for MTX-related leukoencephalopathy.

Keywords: ADORA2A; adenosine; leukoencephalopathy; methotrexate; pharmacogenetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Antimetabolites, Antineoplastic / adverse effects*
Child
Child, Preschool
Female
Hematologic Neoplasms / drug therapy*
Humans
Infant
Leukoencephalopathies / chemically induced*
Leukoencephalopathies / genetics
Male
Methotrexate / adverse effects*
Polymorphism, Single Nucleotide*
Receptor, Adenosine A2A / genetics*
Retrospective Studies
Risk

Substances

Antimetabolites, Antineoplastic
Receptor, Adenosine A2A
Methotrexate