Xu Xinran, Gammon Marilie D, Zhang Heping, Wetmur James G, Rao Manlong, Teitelbaum Susan L, Britton Julie A, Neugut Alfred I, Santella Regina M, Chen Jia
Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Carcinogenesis. 2007 Jul;28(7):1504-9. doi: 10.1093/carcin/bgm061. Epub 2007 Mar 19.
One-carbon metabolism facilitates the crosstalk between genetic and epigenetic processes and plays critical roles in both DNA methylation and DNA synthesis, making it a good candidate for studying the risk of breast cancer. We previously reported that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) in one-carbon pathway were associated with breast cancer risk in the population-based Long Island Breast Cancer Study Project. Herein, we systematically investigated putatively functional polymorphisms of seven other one-carbon-metabolizing genes in relation to the breast cancer risk in the same population. Except for a slight indication of increased risk of breast cancer associated with the double repeat (2R) allele in the thymidylate synthase (TYMS) 5'-untranslated region (UTR) (P, trend = 0.07), polymorphisms in the other six genes did not substantially modify the risk of breast cancer, or did they modify the risk associated with dietary intakes of folate and related B vitamins. However, we observed a significant multiplicative interaction between the MTHFR 677C>T and the TYMS 5'-UTR polymorphisms (P = 0.02). We used a recursive partitioning method, RTREE, in an attempt to tease out important or rate-limiting genes encoding these intricately related enzymes. Results from RTREE analyses indicate that MTHFR and TYMS are the two leading rate-limiting enzymes in the pathway, consistent with our epidemiological findings. Our findings underscore the importance of one-carbon metabolism in breast cancer etiology. Although the pathway is a network of interrelated enzymes, redundancy exists; evaluating the rate-limiting enzyme and its interaction with environment and other genes within the same pathway is critical in assessing breast cancer risk.
一碳代谢促进了遗传和表观遗传过程之间的相互作用，在DNA甲基化和DNA合成中都起着关键作用，使其成为研究乳腺癌风险的一个良好候选对象。我们之前在基于人群的长岛乳腺癌研究项目中报告，一碳途径中的亚甲基四氢叶酸还原酶（MTHFR）多态性与乳腺癌风险相关。在此，我们系统地研究了同一人群中其他七个一碳代谢基因的推定功能性多态性与乳腺癌风险的关系。除了胸苷酸合成酶（TYMS）5'-非翻译区（UTR）中的双重复（2R）等位基因与乳腺癌风险略有增加的迹象相关（P，趋势=0.07）外，其他六个基因的多态性并未实质性改变乳腺癌风险，也未改变与叶酸及相关B族维生素饮食摄入相关的风险。然而，我们观察到MTHFR 677C>T与TYMS 5'-UTR多态性之间存在显著的相乘交互作用（P = 0.02）。我们使用递归划分方法RTREE，试图找出编码这些复杂相关酶的重要或限速基因。RTREE分析结果表明，MTHFR和TYMS是该途径中的两个主要限速酶，与我们的流行病学发现一致。我们的发现强调了一碳代谢在乳腺癌病因学中的重要性。尽管该途径是一个由相互关联的酶组成的网络，但存在冗余；评估限速酶及其与同一途径内环境和其他基因的相互作用对于评估乳腺癌风险至关重要。
