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Methylenetetrahydrofolate reductase (MTHFR) in head and neck cancer development and treatment


Methylenetetrahydrofolate Reductase (MTHFR) is an key enzyme involved in folate pathway that is responsible to conversion of 5,10 methylenete¬trahydrofolate (5,10 MTHFR) into 5- methyltetrahydrofolate (5-MTHFR). 5-MTHFR is the main circulating form of folate responsible to operates in epigenetic process of DNA methylation that is involved in the physiological control of genetic expression. The substrate of MTHFR can serve as a source of carbon units for the conversion of desoxiuridine (dUMP) to desoxitimidine (dTMP) by thymidylate synthase or it is converted to 10-formyltetrahydrofolate (10-formylTHF) for de novo purine synthesis. Genetic polymorphisms in MTHFR gene as the substitution of cytosine to thymine at the nucleotide position 677 of MTHFR gene (MTHFR C677T) and the substitution of adenine to cytosine at the nucleotide position 1298 of MTHFR gene (MTHFR A1298C) are associated to alterations in MTHFR gene expression. These alterations may result in changes in DNA methylation and consequently in the development of head and neck cancer (HNC) and in the tumor resistance to treatment. Antifolate chemotherapeutics such as 5-fluorouracil (5-FU) and methotrexate (MTX) utilized for HNC treatment act inhibiting the purine and pyrimidine pathways, essential to DNA synthesis and cell growth, by blocking enzymes codified by genes involved in folate metabolism. Studies show these antifolate chemotherapies can be associated with different responses to treatment and serious toxicities resulting in treatment interruption or discontinuation, impacting disease outcome. Based on the above data, the objectives of this chapter is to explore and describe literature data on the involvement of MTHFR gene in HNC development and treatment outcome. (AU)

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