Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

The central role of 5,10-methylenetetrahydrofolate reductase ( MTHFR) and methylenetetrahydrofolate dehydrogenase ( MTHFD1) in folate metabolism renders polymorphisms in genes encoding these enzymes potential modulators of therapeutic response to antifolate chemotherapeutics. The analysis of 201 children treated with methotrexate for childhood acute lymphoblastic leukemia ( ALL) showed that patients with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 variant had a lower probability of event-free survival (EFS) in univariate analysis ( hazard ratio (HR) = 2.2, 95% confidence interval (CI), 1.0 - 4.7 and 2.8, 95% CI, 1.1 - 7.3, respectively). Multivariate analysis supported only the role of the MTHFR variant ( HR = 2.2, 95% CI, 0.9 - 5.6). However, the association of both genes with ALL outcome appears to be more obvious in the presence of another event-predisposing variant belonging to the same path of drug action. The combined effect of a thymidylate synthase (TS) triple repeat associated with increased TS levels, with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 allele, resulted in a highly significant reduction of EFS (multivariate HR = 9.0, 95% CI, 1.9 - 42.8 and 8.9, 95% CI, 1.8 - 44.6, respectively). These results reveal the role of gene - gene interactions within a folate pathway, and how they can correlate with relapse probabilities in ALL patients.