The clinical significance of methylenetetrahydrofolate reductase (MTHFR) polymorphisms in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Genetic polymorphisms in the folate metabolic pathway may contribute to the susceptibility to childhood ALL because they affect the DNA synthesis, methylation, and repair. The most common polymorphisms are methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C. The current study aimed at detecting the frequency of these two genetic polymorphisms in de novo ALL patients, and to clarify their impact on the response to induction chemotherapy, as well as treatment toxicity. MTHFR C677T and A1298C polymorphisms were tested in 30 de novo ALL patients by restriction fragment length polymerase chain reaction technique. Thirty normal age- and sex-matched subjects were subjected to the same analysis as a control group. The frequency of MTHFR A1298C gene polymorphism was significantly lower in ALL patients than the controls thus showing a protective effect. The two polymorphisms had no effect on the response to induction chemotherapy. As regards the treatment toxicity, MTHFR C677T polymorphism was associated with marked thrombocytopenia, while A1298C polymorphism was associated with hepatic toxicity. Identifying predictors of methotrexate sensitivity may lead to the development of individualized treatment strategies with improved efficacy and reduced toxicity as well as adjusting the initial methotrexate dose.