Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma
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.
Article: Genetic variants of methionine metabolism and X-ALD phenotype generation: results of a new study sample.[show abstract] [hide abstract]
ABSTRACT: X-linked adrenoleukodystrophy (X-ALD) is the most common inherited leukodystrophy. Nevertheless, no genotype-phenotype correlation has been established so far. Unidentified modifier genes or other cofactors are suspected to modulate phenotype and prognosis. We recently described polymorphisms of methionine metabolism as possible disease modifiers in X-ALD. To retest these findings, we analyzed 172 new DNA samples of X-ALD patients from different populations (France, Germany, USA, China) by genotyping eight genetic variants of methionine metabolism, including DHFR c.594+59del19bp, CBS c.844_855ins68, MTR c.2756A>G, MTHFR c.677C>T and c.1298A>C, MTRR c.60A>G, RFC1 c.80G>A, and Tc2 c.776C>G. We compared three X-ALD phenotypes: childhood-onset cerebral demyelinating inflammatory type (CCALD; n = 82), adulthood onset with focal cerebral demyelination (ACALD; n = 38), and adulthood onset without cerebral demyelination (AMN; n = 52). The association of genotypes and phenotypes was analyzed with univariate two-sided Pearson's chi(2). In the comparison between AMN and CCALD, the G allele of Tc2 c.776C>G was associated with X-ALD phenotypes (chi(2) = 6.1; P = 0.048). The prevalence of the GG genotype of Tc2 c.776C>G was higher in patients with CNS demyelination compared to those without CNS demyelination (chi(2) = 4.42; P = 0.036). The GG genotype was also more frequent in CCALD compared to AMN (chi(2) = 4.7; P = 0.031). The other polymorphisms did not show any significant associations in this study sample. Whereas the influence of other polymorphisms of methionine metabolism was not confirmed, the present study supports the previously made observation that the Tc2 genotype contributes to X-ALD phenotype generation.Journal of Neurology 04/2009; 256(8):1277-80. · 3.47 Impact Factor