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


Linnebank, M; Moskau, S; Jurgens, A; Simon, M; Semmler, A; Orlopp, K; Glasmacher, A; Bargart, C; Vogt-Schaden, M; Urbach, H; Schmidt-Wolf, I G; Pels, H; Schlegel, U (2009). Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma. Neuro-Oncology, 11(1):2-8.

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 (chi(2)=8.67; p=0.013; df=2), the AA genotype of methylenetetrahydrofolate reductase c.1298A>C (chi(2)=13.5; p=0.001; df=2) and the GG genotype of transcobalamin 2 c.776C>G (chi(2)=19.73; p<0.001) in addition to male gender (chi(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.

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 (chi(2)=8.67; p=0.013; df=2), the AA genotype of methylenetetrahydrofolate reductase c.1298A>C (chi(2)=13.5; p=0.001; df=2) and the GG genotype of transcobalamin 2 c.776C>G (chi(2)=19.73; p<0.001) in addition to male gender (chi(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.

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26 citations in Web of Science®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:February 2009
Deposited On:15 Jun 2009 07:48
Last Modified:05 Apr 2016 12:34
Publisher:Oxford University Press
ISSN:1522-8517
Publisher DOI:10.1215/15228517-2008-082
PubMed ID:18806228
Permanent URL: http://doi.org/10.5167/uzh-5562

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