Genetic polymorphisms and gene expression of one-carbon metabolizing enzymes and their relation to breast cancer

Abstract

BackgroundBreast cancer is considered the leading cause of cancer-related death among Egyptian women (15.41%). One of the common BC risk factors is the genetic factor. One-carbon metabolism is one of the pathways reported to increase BC risk by influencing DNA synthesis and methylation. Methyl tetrahydrofolate reductase (MTHFR), thymidylate synthase (TYMS) and DNA methyltransferase (DNMT) enzymes are key enzymes in one-carbon metabolism directly and through influencing folate metabolism. We aimed to study the association of the gene expression level and polymorphisms of MTHER C677T (rs1801133), TYMS (rs45445694), TYMS 3′UTR 1494del6 and ΔDNMT3B − 149C>T with breast cancer risk in a sample of Egyptian women.MethodsThis study was conducted on one hundred female breast cancer patients. Genotyping and gene expression of the MTHFR and TYMS (1494del6, rs45445694) and DNMT3B genes were performed.ResultsThere was no significant difference (OR 1.493; 95% CI 0.78–2.84; P = 0.288) in the frequency of the MTHFR (C677T) genotypes between breast cancer patients and control subjects and no significant difference in the frequency of the MTHFR mutant T allele. TYMS tandem repeats showed a significant difference (OR 2.232; CI 1.21–4.12; P = 0.01) in the frequency of the genotype 2R/3R among breast cancer patients and control subjects; however, the frequency of the 2R allele was not significantly different from that of the 3R allele (OR 1.461; 95% CI 0.96–2.21; P = 0.073). TYMS 3′-UTR 1494del6 showed a significant difference in the distribution of (+ 6/ + 6), (+ 6/− 6) and (− 6/− 6) genotypes between the patient and control groups (P ≤ 0.001*), and its corresponding mutant allele showed P value ≤ 0.001, 95% CI = 1.64–3.76 and OR = 2.483. The expression of MTHFR was downregulated by 0.62-fold in all malignant tissues compared to normal adjacent tissues (0.57 ± 0.20, P < 0.001*). On the other hand, no significant difference (P = 0.143) in the expression level of TYMS was found. Gene expression of DNMT3B was upregulated by 1.65-fold in all breast cancerous tissue samples compared with the control normal adjacent tissue with mean ± SD of 1.81 ± 0.63. (P ≤ 0.001*).ConclusionThe current study showed that the 2R/3R TYMS allele and DNMT3B (− 149C>T) SNP are associated with a high risk of breast cancer and that there is a correlation between the 3′-UTR 1494del6 polymorphism (genotype − 6/− 6) and breast cancer risk. A significant reduction was found in the MTHFR gene expression level in BC compared with control tissues, and the DNMT3B (− 149C>T) SNP did affect the DNMT3B expression level.