Abstract
Folate (vitamin B9) is found in some water-soluble foods or as a synthetic form of folic acid and is involved in many essential biochemical processes. Dietary folate is converted into tetrahydrofolate, a vital methyl donor for most methylation reactions, including DNA methylation. 5,10-methylene tetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate metabolism pathway that converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which produces a methyl donor for the remethylation of homocysteine to methionine. MTHFR polymorphisms result in reduced enzyme activity and altered levels of DNA methylation and synthesis. MTHFR polymorphisms have been linked to increased risks of several pathologies, including cancer. Breast cancer, gliomas and gastric cancer are highly heterogeneous and aggressive diseases associated with high mortality rates. The impact of MTHFR polymorphisms on these tumors remains controversial in the literature. This review discusses the relationship between the MTHFR C677T and A1298C polymorphisms and the increased risk of breast cancer, gliomas, and gastric cancer. Additionally, we highlight the relevance of ethnic and dietary aspects of population-based studies and histological stratification of highly heterogeneous tumors. Finally, this review discusses these aspects as potential factors responsible for the controversial literature concerning MTHFR polymorphisms.
Highlights
Folate is a water-soluble vitamin found in some foods or in a synthetic form used in fortification and dietary supplementation programs [1,2]
Low levels of folate and/or reduced enzyme activity of the main proteins involved in folate metabolism may result in limiting the substrate for methionine synthase, affecting the remethylation pathway and resulting in a high concentration of homocysteine in the plasma; high plasma levels of homocysteine have been linked to several types of human cancers [11,12,13,14,15,16,17]
We detailed studies with controversial results regarding the impact of methylene tetrahydrofolate reductase (MTHFR) polymorphisms on breast cancer, glioma and gastric cancer risk
Summary
Folate is a water-soluble vitamin (vitamin B9) found in some foods (e.g., okra, broccoli, asparagus, lentils, and spinach) or in a synthetic form (folic acid) used in fortification and dietary supplementation programs [1,2]. Literature reports have demonstrated the impact of folate metabolism on DNA synthesis and methylation, resulting in an increased risk of several cancer types when this pathway is dysregulated In this context, this review discusses the relationship of changes in the folate pathway resulting from the C677T and A1298C polymorphisms of the MTHFR gene with the process of breast, glioma and gastric carcinogenesis. Low levels of folate and/or reduced enzyme activity of the main proteins involved in folate metabolism may result in limiting the substrate for methionine synthase, affecting the remethylation pathway and resulting in a high concen3troaft2i7on of homocysteine in the plasma; high plasma levels of homocysteine have been linked to several types of human cancers [11,12,13,14,15,16,17]. There are two polymorphisms of the MTHFR gene already well described as associated with numerous pathologies: C677T and A1298C [15,27,28]
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