Breast Cancer has been associated with polymorphisms in genes candidate to be disease modifiers, such as CYP19 (Family 19 of the Cytochrome P450), GSTP1 (Glutathione S-Transferase Protein), TP53 (Tumor Protein 53), P21 (Protein 21) , MTHFR (Methylenetetrahydrofolate Reductase) and TYMS (Thymidylate Synthase)  and, which are involved in events such as synthesis, methylation and DNA damage repair, and cellular activation in carcinogen metabolism and the metabolism of anticancer drugs. Gene variations, besides being related to risk factors for the development of BC, they can interfere with gene expression or activity level, and may be associated with different tumor phenotypes tumor [21–23]. The study of genetic variation may influence clinical management and better pharmacogenetic intervention to BC [24, 25].
In the present study it was investigated whether polymorphisms in the TYMS gene, as a molecule with a key role in DNA synthesis, are associated with risk of development of BC as SBC and/or HBC. Although several studies have associated this gene with other cancers (colorectal, lung, pancreatic, gastric, and lymphoma) [26–32], this study is the first to correlate the HBC and SBC forms to polymorphisms in the 5’-UTR region of the TYMS gene in Brazilian population, in this way, is difficult to do association with others studies with similar characteristics.
Studies in other populations have found significative associations between the TYMS gene 5’-UTR variations and the BC development [2, 11, 12]. But the fact that the 2R/2R and 2R/3R variants (in HBC and BC/HBC/SBC, respectively), which would have a protective effect have presented relation, and risk effect, respectively, need to be better studied. What can be explained by the imbalance of Hardy Weinberg found, especially in our control population or by other mechanisms that need to be better studied.
The 3R allele results in greater TYMS activity . Therefore, the 2R/3R genotype should have intermediate activity. As the TYMS competes with MTHFR (Methylenetetrahydrofolate reductase) at the cycle of folic acid metabolism, the availability of 5,10-methylene THF (tetrahydrofolate), Trinh et al. (2002) , issued the hypothesis that the 3R variant could affect the levels of 5,10-methylene THF and this could lead to lower cell concentration of S-Adenosyl methionine and consequent decrease in DNA methylation. Thus, DNA hypomethylation, may increase susceptibility gene mutations or alter the expression of genes as protooncogenes or tumor suppressor, or would result in epigenetic changes that may initiate carcinogenesis. The association of TYMS polymorphism has been reinforced in a meta-analysis, being the 3R allele important in the BC risk .
The 3R/3R genotype for the TYMS gene has been associated with high levels of enzyme activity in tumors, and it have been considered to the best prognostic presented by chemosensibilizing (5-Flurouracil, 5-FU) to the BC. It shows the importance of genotypic characterization of the TYMS 5’-UTR of Brazilian population, suggesting that genotype of TYMS gene related to the number of repetitions in tandem can be, at least, partial indicator to the 5-FU chemotherapy [15, 35–39]. The frequency found for triple homozygous (3R/3R), with worse prognosis, was around 16% to 24% in our population with BC, and 36% for the control population. The low number of individuals with the genotype 3R/3R in our population with the disease can be positive, due to chemotherapy efficiency than the other two genotypes (2R/2R and 2R/3R, in more than 75% of cases).
These observations emphasize the biological and clinical importance of the TYMS polymorphisms in relation to response and toxicity to chemotherapy , even more for being related to risk of BC found in this study. Thus, with pharmacogenomic studies it would be possible to understand the action of different drugs in combination with the chemotherapeutic effect and the association with the gene analyzed, and using polymorphisms in the TYMS gene as population biomarkers of severity to different types of cancer, especially the BC.
In our study, the Hardy-Weinberg in control group was not found because we selected only people without BC, and maybe as an important factor, the natural selection acts in the way to put better mechanisms in response to the cancer. In other study realized in our laboratory (data no divulgate) with an aneuploidia and controls we have the same data, the control population (woman) not shows Hardy-Weinberg equilibrium [63 woman; 23 (36.50%), 20 (31.75%), 20 (31.75%), respectively to 2R/2R, 2R/3R and 3R/3R genotypes frequency, p < 0.05]. As a major consideration, we can have a population to analyze the genotype frequency without taking into account a disease as selection factor, as we provide in the present study, as well we include only woman (only with adult advanced age) without BC our historical of the disease.