Effect of methylenetetrahydrofolate reductase 677C→T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients

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Abstract
MTHFR is a critical enzyme that regulates the metabolism of folate and methionine, both of which are important factors in DNA methylation and synthesis. Subjects with the 677C→T variant have impaired remethylation of Hcy to methionine that could determine hyperhomocysteinemia. Remethylation of Hcy into methionine and DNA methylation are also affected by MTX treatment. Thus, a combined effect between MTX and reduced activity of the MTHFR 677C→T polymorphism could occur, leading to toxicity. In a clinical trial, 43 ovarian cancer patients were treated with low doses of MTX. During MTX therapy, 12 patients (27.9%) developed G3/4 WHO toxicity. In these 12 patients, we observed 6 G3/4 thrombocytopenias, 1 G3 neutropenia, 1 G3 anemia, 9 G3 mucositis cases and 1 G4 mucositis case. A significant association was observed between toxicity and TT MTHFR 677 genotype (p < 0.0001). G3/4 toxicity occurred in 10 of 13 (77%), 1 of 17 (6%) and 1 of 13 (8%) patients with the TT, CT and CC MTHFR genotypes, respectively. According to the logistic regression model, patients with the TT genotype had a relative risk of 42.0 (95% CI 4.2–418.6) of developing G3/4 toxicity compared to patients with the CC and CT genotypes. Patients with the TT genotype had Hcy plasma levels after MTX therapy significantly (p = 0.0001) higher than basal levels (mean ± SD = 16.71 ± 4.72 vs. 12.48 ± 3.57 μmol/l); moreover, they also had higher Hcy plasma levels after MTX than patients with other MTHFR 677 genotypes (CC mean ± SD = 9.87 ± 3.61 μmol/l and CT mean ± SD = 11.48 ± 3.13 μmol/l). Finally, significant associations were observed between G3/4 WHO toxicity and higher Hcy plasma levels after MTX treatment (p = 0.0004). In conclusion, our data suggest that the TT MTHFR 677 genotype is associated with marked MTX‐induced hyperhomocysteinemia and could represent a pharmacogenetic marker for toxicity after chronic treatment with low doses of MTX.