DHFR 19-bp insertion/deletion polymorphism and MTHFR C677T in adult acute lymphoblastic leukaemia: is the risk reduction due to intracellular folate unbalancing?

Folate and its derivatives are pivotal for cell cycle and proliferation. They facilitate the crosstalk between DNA synthesis and methylation crucial processes in cancer establishment. Dietary folate or supplements (e.g., folic acid) must be fully reduced by dihydrofolate reductase (DHFR) before entering cell metabolism. DHFR is responsible for dihydrofolate (DHF) to tetrahydrofolate (THF) conversion, as well as for assisting the generation of additional partially reduced folates (i.e., methylene-THF and formyl-THF), which are then transformed into the fully active folate (i.e., methyl-THF) with the help of ethylenetetrahydrofolate reductase (MTHFR). As the main folate isoforms involved in DNA synthesis and methylation are handled by these two key enzymes, alterations in DHFR and/or in MTHFR functions may have detrimental effects on DNA stability and cancer susceptibility.