Molecular Genetics Laboratory, Department of Pathology and Forensic Medicine, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
Anticancer Res. 2012 Nov;32(11):4805-11.
Polymorphisms in genes encoding enzymes of folate metabolism are a focus of breast cancer risk studies due of the role of these enzymes in DNA methylation, synthesis, and repair. MTHFR, encoding for 5,10-methylenetetrahydrofolate reductase, is one of the most studied genes in this regard, but findings are controversial, and the majority of studies have analyzed polymorphisms individually. In this case control study, we examined the combination of the polymorphisms MTHFR C677T and A1298C with MTR A2756G, where MTR, methionine synthase, is an important enzyme of the folate cycle in the methylation pathway. One hundred and forty-two patients with breast cancer and controls were included and the genotypes were determined using PCR-RFLP. In the population studied, individuals carrying the polymorphic allele in the heterozygous state for both enzymes, MTHFR C677T and MTR A2756G, had an increased risk [odds ratio, OR=2.77 (95% confidence interval, CI=1.19-6.52)] for disease, compared to those with the wild genotype. In addition, individuals carrying the MTR 2756 genotype AG had an increased risk when this was combined with the MTHFR 1298 genotype CC [OR=5.13 (95% CI=0.87-38.82)]. No significant results were found from the analyses associating the MTHFR C677T and A1298C genotypes. However, when stratifying the patients by age (50 years old as the cut-off), patients over 50 years old had greater risk, with the presence of both MTHFR polymorphisms in the heterozygous state [OR=5.33 (95% CI=1.42-21.03)]. This study points out the importance of the interactions between the MTHFR C677T, MTHFR A1298C and MTR A2756G polymorphisms, and also highlights the relevance of the MTR A2756G polymorphism and age in breast cancer risk.
叶酸代谢酶基因的多态性是乳腺癌风险研究的焦点，因为这些酶在 DNA 甲基化、合成和修复中起作用。MTHFR 编码 5,10-亚甲基四氢叶酸还原酶，是这方面研究最多的基因之一，但研究结果存在争议，大多数研究都单独分析了多态性。在这项病例对照研究中，我们研究了 MTHFR C677T 和 A1298C 与 MTR A2756G 的多态性组合，其中 MTR，即蛋氨酸合成酶，是甲基化途径中叶酸循环中的重要酶。我们纳入了 142 名乳腺癌患者和对照组，并使用 PCR-RFLP 确定了基因型。在所研究的人群中，与野生基因型相比，两种酶（MTHFR C677T 和 MTR A2756G）杂合状态携带多态性等位基因的个体 [比值比，OR=2.77（95%置信区间，CI=1.19-6.52)]，患病风险增加。此外，当 MTR 2756 基因型 AG 与 MTHFR 1298 基因型 CC 相结合时，AG 基因型个体的患病风险增加 [OR=5.13（95%CI=0.87-38.82)]。MTHFR C677T 和 A1298C 基因型的关联分析未发现显著结果。然而，当按年龄（50 岁为截止点）对患者进行分层时，50 岁以上的患者风险更大，且 MTHFR 两种多态性均为杂合状态 [OR=5.33（95%CI=1.42-21.03)]。本研究指出了 MTHFR C677T、MTHFR A1298C 和 MTR A2756G 多态性之间相互作用的重要性，并强调了 MTR A2756G 多态性和年龄在乳腺癌风险中的相关性。
