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.

Xiayu Wu,Michael Fenech,Ziqing Liang,Xu Wang,Neng Cao,Tianning Zou,Tao Zhou,Weijiang Xu,Juan Ni

doi:10.3390/ijms17071003

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.

Highlights

Folate, vitamin B6 (B6), and vitamin B12 (B12) have been proven to play important roles in the one-carbon metabolism pathway and the prevention of carcinogenesis: (a) in the transformation of homocysteine (Hcy) to methionine for methylation of DNA to ensure gene expression and genomic stability; and (b) in the synthesis of purine precursors and thymidylate of nucleic acid (DNA and RNA) [1,2,3,4]
Because there was no significant difference of growth between 200 and 4800 nmol/L and both cell lines were dead at 0 nmol/L, we selected 6, 12, 24, 48, 96, and 200 nmol/L B6 to culture both lymphocytes from the breast cancer cases and controls in follow-up experiments (Supplementary Figure S1)
We examined the association between genomic stability and cell viability (GSACV) and three enzyme polymorphisms, serine hydroxymethyltransferase (SHMT) C1420T, methionine synthase (MS) A2756G, and MTRR A66G, under B6 deficiency, which was based on functional polymorphisms and previous reports of associations with breast cancer risk

Summary

Introduction

Vitamin B6 (B6), and vitamin B12 (B12) have been proven to play important roles in the one-carbon metabolism pathway and the prevention of carcinogenesis: (a) in the transformation of homocysteine (Hcy) to methionine for methylation of DNA to ensure gene expression and genomic stability; and (b) in the synthesis of purine precursors and thymidylate of nucleic acid (DNA and RNA) [1,2,3,4]. GSH plays a key role of detoxification and protection as a cofactor of GSH peroxidases and GSH S-transferases. It can protect cells from the oxidative damage of nucleic acids, proteins and lipids [7,8,9]. Rodent studies have shown that azoxymethane-induced colon tumorigenesis in mice is suppressed by moderate doses of dietary B6, and B6 can suppress endothelial cell angiogenesis and proliferation in part by restraining DNA topoisomerases and DNA polymerase [10,11]

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