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Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma

University Hospital Bonn, Departments of Neurology (M.L., S.M., A.S.), Neurosurgery (M.S.), Internal Medicine (K.O., A.G., I.G.H.S.-W.), and Radiology (H.U.), Bonn, Germany; University Hospital Zurich, Department of Neurology, Zurich, Switzerland (M.L.); University Hospital Bochum, Knappschaftskrankenhaus, Department of Neurology, Bochum, Germany (A.J., H.P., U.S.); University Hospital Cologne, Department of Radiology, Cologne, Germany (C.B.); University Hospital Heidelberg, Department of Neurology, Heidelberg, Germany (M.V.-S.)

Address correspondence to Michael Linnebank, University Hospital Zurich, Department of Neurology, Frauenklinikstrasse 26, CH-8091, Zurich, Switzerland (Michael.Linnebank{at}usz.ch).

Methotrexate (MTX) is an important anticancer drug and the most efficient chemotherapy component in primary CNS lymphoma (PCNSL). A typical side effect of intravenous high-dose MTX is the occurrence of confluent CNS white matter changes (WMC). Because 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, 10 genetic variants influencing methionine metabolism were analyzed. Pearson's ² 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: methionine metabolism • methotrexate • primary central nervous system lymphoma (PCNSL) • white matter changes

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