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Despite remarkable progress in survival of children with acute lymphoblastic   leukemia (ALL) which has reached about 85%, early toxicity and relapse rate   remain issues that need to to be resolved. Genetic variants are important   factors influencing the metabolism of cytotoxic drugs in ALL treatment.   Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are   under constant scientific interest due to their potential impact on drug   toxicity and relapse rate. We investigated methylenetetrahydrofolate   reductase (MTHFR) c.677C>T and MTHFR c.1298A>C variants as pharmacogenetic   markers of MTX toxicity and predictors of relapse. The study enrolled 161   children with ALL, treated according to the current International   Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of   leukemia and lymphoma protocols. Genotyping was performed using PCRRFLP and   allele-specific PCR assays. Our results revealed similar distributions of   MTHFR c.677C>T and MTHFR c.1298A>C genotypes among 104 healthy individuals as   compared to pediatric ALL patients. A lower incidence of early MTX toxicity   was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A>C   genotypes were not associated with MTX toxicity. Carriers of any MTHFR   c.677C>T and MTHFR c.1298A>C genotypes did not experience decreased overall   survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene   are not involved in leukemogenesis in pediatric ALL. The presence of the   MTHFR c.677TT genotype was recognized as a predictive factor for decreased   MTX toxicity during the intensification phase of therapy. Neither MTHFR   c.677C>T nor MTHFR c.1298A>C genotypes correlated with an increased number of   toxic deaths or relapse rate. Our study emphasizes the importance of   implementing pharmacogenetic markers in order to optimize pediatric ALL   therapy. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III 41004

archives of biological sciences

Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia