Association of genetic variants of methionine metabolism with MTX-induced CNS white matter changes in patients with primary central nervous system lymphoma

¹ University Hospital Bonn, Department of Neurology, Bonn, Germany; University Hospital Zurich, Department of Neurology, Frauenklinikstrasse 26, CH-8091, Zurich, Switzerland
² University Hospital Bonn, Department of Neurology, Bonn, Germany
³ University Hospital Bochum, Knappschaftskrankenhaus, Department of Neurology, Bochum, Germany
⁴ University Hospital Bonn, Department of Neurosurgery, Bonn, Germany
⁵ University Hospital Bonn, Department of Internal Medicine, Bonn, Germany
⁶ University Hospital Cologne, Department of Radiology, Cologne, Germany
⁷ University Hospital Heidelberg, Department of Neurology, Heidelberg, Germany
⁸ University Hospital Bonn, Department of Radiology, Bonn, Germany

^* To whom correspondence should be addressed. E-mail: Michael.Linnebank{at}usz.ch.

	Abstract

Methotrexate (MTX) is an important anticancer drug and the most efficient chemotherapy component in primary central nervous system lymphoma (PCNSL). A typical side effect of intravenous high-dose MTX is the occurrence of confluent CNS white matter changes (WMC). Since MTX directly interferes with methionine metabolism, we analyzed the impact of genetic variants of methionine metabolism on the occurrence of WMC as a model of MTX toxicity. In a retrospective analysis of 68 PCNSL patients treated with MTX-based polychemotherapy with (n=42) or without (n=26) intraventricular treatment, ten genetic variants influencing methionine metabolism were analyzed. Pearson's Chi-square test and multinominal regression analysis were used to define the relevance of these genetic variants for the occurrence of WMC. In this patient sample, the occurrence of WMC was significantly predicted by the TT genotype of methylenetetrahydrofolate reductase c.677C>T (²=8.67; p=0.013; df=2), the AA genotype of methylenetetrahydrofolate reductase c.1298A>C (²=13.5; p=0.001; df=2) and the GG genotype of transcobalamin 2 c.776C>G (²=19.73; p<0.001) in addition to male gender (²=11.95; p=0.001). These data strengthen the hypothesis that MTX effects are influenced by methionine metabolism which may offer new strategies to improve MTX-based therapies.

Key Words: white matter-changes, methotrexate, primary central nervous system lymphoma (PCNSL), methionine-metabolism

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