Nutritional and Genetic Markers of Breast Cancer

我们建议对营养生物标记物和相应的基因变异进行前瞻性研究。 参与单碳代谢及其交互作用对女性乳腺癌风险的影响 健康研究(WHS)。将确定和确认总共1100例乳腺癌病例 在28345名有存档的基线血液样本的参与者中。我们将分析五种营养成分 生物标志物(即血浆叶酸、维生素B6和B12、半胱氨酸和同型半胱氨酸)。应用最新情况- ART基因分型技术和统计方法，我们将评估功能变异并确定 12个相关候选基因的单倍型结构。这些基因将包括谷氨酸- 半胱氨酸连接酶(GCLC[催化亚基]和GCLM[调节亚单位])，叶酸代谢基因 (还原叶酸载体-1[RFC]，5，10-亚甲基四氢叶酸还原酶[MTHFR]，蛋氨酸 合酶[MTR]、蛋氨酸合成酶还原酶[MTRR]、丝氨酸羟甲基转移酶[SHMT1]、 和胸苷合成酶[TYMS])、儿茶酚-O-甲基转移酶(COMT)和DNA修复基因(X- 射线修复交叉互补[XRCC]-1、2和3)。至少有三条相互关联的路径 这些标记物可能与乳腺癌风险有关。首先，叶酸和维生素B12会影响 甲基的可用性，因此可以防止异常的DNA甲基化。第二，叶酸和维生素 B6和B12影响DNA的合成和修复。第三，半胱氨酸是合成半胱氨酸的关键氨基酸 谷胱甘肽(GSH)，重要的细胞内抗氧化剂和解毒剂。Gclc和Gclm基因 编码半胱氨酸生物合成谷胱甘肽的限速酶。现有数据还表明， 叶酸与酒精摄入量相互作用，影响患乳腺癌的风险。然而，没有已发布的数据显示 评估GCLC、GCLM、RFC、MTR、MTRR、SHMT1和TYMS基因多态是否影响乳房 癌症风险。这项研究的发现将有助于为公共卫生建议提供基础 关于叶酸和维生素B的最佳摄入量，建议新的预防策略，并确定 高危人群。WHS的几个独特特征，包括其前瞻性设计、大样本 大小、持续时间长、随访率高、可获得储存的血液样本、全面 协变量信息和成本效率，使该队列成为 乳腺癌的病因学调查。

We propose to conduct a prospective study of nutritional biomarkers and corresponding gene variants involved in one-carbon metabolism¿and their interactive effects¿on breast cancer risk in the Women's Health Study (WHS). A total of 1,100 incident cases of breast cancer will be identified and confirmed among 28,345 participants with archived baseline blood specimens. We will assay five nutritional biomarkers (i.e. plasma folate, vitamins B6 and B12, cysteine, and homocysteine). Applying state-of-the- art genotyping technology and statistical methods, we will evaluate functional variants and determine the structure ofhaplotypes in twelve relevant candidate genes. These genes will include glutamate- cysteine ligase (GCLC [catalytic subunit] and GCLM[regulatory subunif]), folate-metabolizing genes (reducedfolate carrier-1[RFC], 5,10-methylene-tetrahydrofolate reductase [MTHFR], methionine synthase [MTR], methionine synthase reductase [MTRR], serine hydroxymethyltransferase [SHMT1], and thymidylate synthase [TYMS]), catechol-O-methyltransferase (COMT), and DNA repair genes (X- ray repair cross complementing [XRCC]-1, 2, and 3). There are at least three interrelated pathways by which these markers may be associated with breast cancer risk. First, folate and vitamin B12 affect methyl group availability and may thus prevent abnormal DNA methylation. Second, folate and vitamins B6 and B12 influence DNA synthesis and repair. Third, cysteine is the key amino acid in the synthesis of glutathione (GSH), an important intracellular antioxidant and detoxifying agent. GCLC and GCLM genes encode a rate-limiting enzyme for GSH biosynthesis from cysteine. Available data also suggest that folate interacts with alcohol intake to affect breast cancer risk. However, no published data have evaluated whether GCLC, GCLM, RFC, MTR, MTRR, SHMT1, and TYMS polymorphisms affect breast cancer risk. Findings from this study will help provide a basis for public health recommendations regarding optimal levels of folate and B vitamin intakes, suggest new prevention strategies, and identify high-risk individuals. Several unique features of the WHS, including its prospective design, large sample size, long duration, high follow-up rates, availability of stored blood specimens, comprehensive covariate information, and cost efficiency, make this cohort a valuable and exceptional resource for the etiologic investigation of breast cancer.