Folic acid, polymorphism of methyl-group metabolism genes, and DNA methylation in relation to GI carcinogenesis

Abstract

DNA methylation is the main epigenetic modification after replication in humans. DNA (cytosine-5)-methyltransferase (DNMT) catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to C5 of cytosine within CpG dinucleotide sequences in the genomic DNA of higher eukaryotes. There is considerable evidence that aberrant DNA methylation plays an integral role in carcinogenesis. Folic acid or folate is crucial for normal DNA synthesis and can regulate DNA methylation, and through this, it affects cellular SAM levels. Folate deficiency results in DNA hypomethylation. Epidemiological studies have indicated that folic acid protects against gastrointestinal (GI) cancers. Methylene-tetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are the enzymes involved in folate metabolism and are thought to influence DNA methylation. MTHFR is highly polymorphic, and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. Two common MTHFR polymorphisms, 677CT (or 677TT) and A1298C, and an MS polymorphism, A-->G at 2756, have been identified. Most studies support an inverse association between folate status and the rate of colorectal adenomas and carcinomas. During human GI carcinogenesis, MTHFR is highly polymorphic, and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level, as well as aberrant methylation.

Direct Genotyping of Single Nucleotide Polymorphisms in Methyl Metabolism Genes Using Probe-Free High-Resolution Melting Analysis

“…It has been shown that a deficiency of this nutrient results in DNA hypomethylation. The role of folate and the above germ-line variants in relation to cancer has been reviewed (16,17).…”

Folate intake, Methylenetetrahydrofolate Reductase Polymorphisms in Association with the Prognosis of Esophageal Squamous Cell Carcinoma

“…It facilitates the conversion of 5, 10-methylene THF to 5-methyl THF, and leads point mutations and/or chromosomal breaks. Also, it may cause decline of 5-methyl THF to induce a decrease of the conversion of homocysteine to methionine, which could result in a carcinogenesis process of DNA hypomethylation (Stern et al, 2000;Fang and Xiao, 2003;Blount et al, 2007). Approximately 60 polymorphisms have been described in the MTHFR gene (Leclerc and Rozen, 2007).…”

Early Pregnancy Screening for Complications of Pregnancy: Proteomic Profiling Approaches

“…blood pressure, hyperglycemia (Brasacchio et al, 2009);(El-Osta et al, 2008); ischemia (Kumral et al, 2009;Parker et al, 2008)) and/or diet (e.g. butyrate (Vidali et al, 1978), organosulfur (Tissenbaum & Guarente, 2001), dietary polyphenols (Howitz et al, 2003), folate, and choline (Fang & Xiao, 2003)) may induce adaptive or compensatory epigenetic modifications within the placental and/or fetal genomes. Thus, periconceptional and early pregnancy events may affect the placental and/or fetal epigenome.…”