Role of the MTHFR polymorphisms in cancer risk modification and treatment.

The role of folate, a water-soluble B vitamin, and single nucleotide polymorphisms (SNPs) in the folate metabolic pathway in human health and disease has been rapidly expanding. Recently, functionally significant SNPs in 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme for intracellular folate homeostasis and metabolism, have been identified and characterized. The MTHFR SNPs are ideal candidates for investigating the role of SNPs in cancer risk modification and treatment because of their well-defined and highly relevant biochemical effects on intracellular folate composition and one-carbon transfer reactions. Indeed, a large body of molecular epidemiologic evidence suggests that the MTHFR 677 variant T allele is associated with cancer risk in a site-specific manner. Furthermore, biologically plausible mechanisms based on the functional consequences of changes in intracellular folate cofactors resulting from the MTHFR 677T variant exist to readily explain cancer risk modification associated with this variant. In addition, a growing body of in vitro and clinical evidence suggests that the MTHFR SNPs may be an important pharmacogenetic determinant of response to and toxicity of 5-fluorouracil (5FU) and methotrexate (MTX)-based cancer and anti-inflammatory chemotherapy. Furthermore, studies suggest that MTHFR inhibition may be a potential target for increasing chemosensitvity of cancer cells to 5FU-based chemotherapy. Because the MTHFR SNPs are prevalent and MTX and 5FU are widely used for the treatment of common cancers and inflammatory conditions, the pharmacogenetic role of the MTHFR SNPs has significant clinical implications. MTHFR SNPs may play an important role in providing rational, effective and safe tailored treatment to patients with cancer and inflammatory disorders requiring 5FU and MTX-based therapy. As such, largescale human studies and in vitro mechanistic studies are warranted to clarify the pharmacogenetic role of the MTHFR SNPs.