The Role of Genetic Polymorphisms as Related to One-Carbon Metabolism, Vitamin B6, and Gene–Nutrient Interactions in Maintaining Genomic Stability and Cell Viability in Chinese Breast Cancer Patients

Abstract

Folate-mediated one-carbon metabolism (FMOCM) is linked to DNA synthesis, methylation, and cell proliferation. Vitamin B6 (B6) is a cofactor, and genetic polymorphisms of related key enzymes, such as serine hydroxymethyltransferase (SHMT), methionine synthase reductase (MTRR), and methionine synthase (MS), in FMOCM may govern the bioavailability of metabolites and play important roles in the maintenance of genomic stability and cell viability (GSACV). To evaluate the influences of B6, genetic polymorphisms of these enzymes, and gene–nutrient interactions on GSACV, we utilized the cytokinesis-block micronucleus assay (CBMN) and PCR-restriction fragment length polymorphism (PCR-RFLP) techniques in the lymphocytes from female breast cancer cases and controls. GSACV showed a significantly positive correlation with B6 concentration, and 48 nmol/L of B6 was the most suitable concentration for maintaining GSACV in vitro. The GSACV indexes showed significantly different sensitivity to B6 deficiency between cases and controls; the B6 effect on the GSACV variance contribution of each index was significantly higher than that of genetic polymorphisms and the sample state (tumor state). SHMT C1420T mutations may reduce breast cancer susceptibility, whereas MTRR A66G and MS A2756G mutations may increase breast cancer susceptibility. The role of SHMT, MS, and MTRR genotype polymorphisms in GSACV is reduced compared with that of B6. The results appear to suggest that the long-term lack of B6 under these conditions may increase genetic damage and cell injury and that individuals with various genotypes have different sensitivities to B6 deficiency. FMOCM metabolic enzyme gene polymorphism may be related to breast cancer susceptibility to a certain extent due to the effect of other factors such as stress, hormones, cancer therapies, psychological conditions, and diet. Adequate B6 intake may be good for maintaining genome health and preventing breast cancer.

Effect of Bioactive Nutriments in Health and Disease: The Role of Epigenetic Modifications

“…Paradoxically, hypermethylation was induced in DNA sequences coding for tumor suppressor genes. The changes in the methylation processes exerted by an increase in DNMTs (DNA methyltransferases) activity may explain the hypermethylation observed in these experimental models, whereas the stimulation of MBD2 and MBD4 (methyl-CpG-binding domain proteins) may explain the decrease on DNA methylation favoring the expression of oncogenes and prometastatic genes [9,10].…”

Nutrigenômica Como Ferramenta Preventiva De Doenças Crônicas Não Transmissíveis

“…Por meio da suplementação da dieta materna com colina, betaína, ácido fólico, vitamina B12, metionina e zinco ocorreu um aumento da metilação do DNA, coincidindo com menor suceptibilidade a obesidade, diabetes e câncer (TRUJILLO;DAVIS;MILNER, 2006). Wu et al (2016) observaram que a deficiência de vitamina B6 diminui a apoptose e aumenta a frequência de necrose in vitro. Os pacientes com câncer de mama são mais sensíveis à deficiência de B6 que os controles em relação à estabilidade genômica, sugerindo que uma baixa ingestão de B6 a longo prazo poderia aumentar o dano ao DNA e exacerbar ainda mais a instabilidade genômica.…”

Folic acid deficiency increases sensitivity to DNA damage by glucose and methylglyoxal

“…This process is required for the synthesis of deoxythymidine monophosphate from deoxyuridine monophosphate and remethylation of homocysteine to methionine and ultimately S -adenosyl methionine required for maintenance of DNA methylation patterns [ 2 ]. Deficiency in these vitamins is associated with genomic instability, caused primarily by uracil misincorporation into DNA and induction of micronuclei (MNi), which can be measured by the cytokinesis block micronucleus cytome (CBMNcyt) assay [ 1 , 3 , 4 ]. Moreover, deficiencies in pyridoxine and folic acid are associated with whole chromosome loss events, chromosomal rearrangement, and telomere attrition [ 4 , 5 ].…”

“…Deficiency in these vitamins is associated with genomic instability, caused primarily by uracil misincorporation into DNA and induction of micronuclei (MNi), which can be measured by the cytokinesis block micronucleus cytome (CBMNcyt) assay [ 1 , 3 , 4 ]. Moreover, deficiencies in pyridoxine and folic acid are associated with whole chromosome loss events, chromosomal rearrangement, and telomere attrition [ 4 , 5 ]. Interestingly, deficiencies in these vitamins are associated with increased cellular susceptibility to DNA damage by other genotoxins.…”