Abstract
5,10-Methylenetrahydrofolate reductase (MTHFR), a key enzyme for folate metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is located at the end of the short arm (1p36.3). Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were mainly described with decreased enzymatic activity and an alteration of intracellular folate distribution. Osteosarcomas are currently treated with high dose of methotrexate (MTX). The decreased enzyme activity of MTHFR theoretically could increase the drug action of MTX and at the same time increase toxic and side effect. Germline variants of C677T and A1298C were studied in 59 osteosarcoma patients, with whom the A1298C is detected with particularly low rate of mutant genotype (N = 1, 0.8%) and could not proceed with statistical calculations. 15 patients were wild type of C677T (CC, 25.4%), 20 were heterozygous mutant genotype (CT, 33.9%) and 24 were homozygous mutant genotype (TT, 40.7%). Patients harboring the TT/CT genotype had the same progression-free survival and tumor necrosis rate in comparison with patients having the CC genotype (P = 0.349 and P = 0.465 respectively). And the C677T polymorphisms had no significant correlation with MTX initial plasma concentration (P = 0.867; r = 0.024) and delayed elimination (P = 0.305; r = −0.136). However patients with mutant genotype of C677T were associated with higher degree of liver toxicity (P = 0.043) and fever reaction of MTX (P = 0.050) while G3/G4 hematologic toxicity were more likely to be noticed with TT than CT/CC (P = 0.095). The study suggests that genetic polymorphism of MTHFR C677T in the MTX metabolic pathway seems to be associated with the trend for more side effects statistically, but has no obvious effect on histologic response and survival.
Highlights
Pharmacogenetics represents a promising future for the individualization of therapy
The study suggests that genetic polymorphism of Methylenetrahydrofolate reductase (MTHFR) C677T in the MTX metabolic pathway seems to be associated with the trend for more side effects statistically, but has no obvious effect on histologic response and survival
From January 2012 to May 2015, 62 participants were enrolled; one patient dropped the first-line chemotherapy because of rapidly tumor progression and two patients were lost to follow-up, whom had all been excluded from this study
Summary
Several genetic polymorphisms and haplotypes have been investigated in an attempt to optimize therapy with specific drugs. 5,10-Methylenetrahydrofolate reductase (MTHFR), which has been described as being located at the branch point in directing folate metabolites toward remethylation of homocysteine and restraint of DNA and RNA biosynthesis [2], catalyses the irreversible conversion of. This gene consists of two well-described polymorphisms: C677T and A1298C [3, 4]. It is reported that the MTHFR C677T genotype decreases by 30 percent of the MTHFR enzyme activity in vitro compared with the wild type [5]. The A1298C causes conformational changes within the MTHFR enzyme that alters the activity of the enzyme but with a lower degree compared to C677T [4]
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