Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma.
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 chi(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 (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.
Linnebank
Michael
M
University Hospital Bonn, Department of Neurology, Bonn, Germany. Michael.Linnebank@usz.ch
Moskau
Susanna
S
Jürgens
Annika
A
Simon
Matthias
M
Semmler
Alexander
A
Orlopp
Katjana
K
Glasmacher
Axel
A
Bangard
Christopher
C
Vogt-Schaden
Marlies
M
Urbach
Horst
H
Schmidt-Wolf
Ingo G H
IG
Pels
Hendrik
H
Schlegel
Uwe
U
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D003541:Cystathionine beta-Synthase / Q000235:genetics; D005260:Female; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D008715:Methionine / Q000378:metabolism*; D051150:Methionine Sulfoxide Reductases; D008727:Methotrexate / Q000009:adverse effects*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008840:Microfilament Proteins; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics; D009709:Nucleotide Deaminases / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D050053:TRPM Cation Channels / Q000235:genetics; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014155:Transcobalamins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D008840:Microfilament Proteins; D009097:Multienzyme Complexes; D050053:TRPM Cation Channels; C404409:TRPM5 protein, human; D014155:Transcobalamins; D014157:Transcription Factors; C113120:inosine monophosphate synthase; D008715:Methionine; D010088:Oxidoreductases; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013762:Tetrahydrofolate Dehydrogenase; C120376:MSRB2 protein, human; D051150:Methionine Sulfoxide Reductases; D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases; D003541:Cystathionine beta-Synthase; D008727:Methotrexate