Nutritional and Genetic Markers of Breast Cancer

描述（由申请人提供）：我们建议在妇女健康研究（WHS）中进行一项前瞻性研究，研究涉及一碳代谢的营养生物标志物和相应的基因变异及其相互作用对乳腺癌风险的影响。在28,345名具有存档基线血液标本的参与者中，将确定和确认总共1,100例乳腺癌病例。我们将检测五种营养生物标志物（即血浆叶酸、维生素B6和B12、半胱氨酸和同型半胱氨酸）。应用最先进的基因分型技术和统计学方法，我们将评估功能变体，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 [调节亚基]），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]、甲硫氨酸合成酶[MTR]、甲硫氨酸合成酶还原酶[MTRR]、丝氨酸羟甲基转移酶[SHMT 1]和胸苷酸合成酶[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）。至少有三种相互关联的途径，这些标志物可能与乳腺癌风险相关。首先，叶酸和维生素B12影响甲基的可用性，从而可以防止异常的DNA甲基化。其次，叶酸和维生素B6和B12影响DNA的合成和修复。第三，半胱氨酸是合成谷胱甘肽（GSH）的关键氨基酸，谷胱甘肽是一种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GSH的限速酶。现有数据还表明，叶酸与酒精摄入量相互作用，影响乳腺癌的风险。然而，没有发表的数据评估GCLC，GCLM，RFC，MTR，MTRR，SHMT1和TYMS多态性是否影响乳腺癌的风险。这项研究的结果将有助于为公众健康提供有关叶酸和B族维生素摄入量最佳水平的建议，提出新的预防策略，并确定高危人群。WHS的几个独特的特点，包括其前瞻性设计，大样本量，持续时间长，高随访率，储存的血液标本的可用性，全面的协变量信息，和成本效益，使这个队列的乳腺癌病因调查的宝贵和特殊的资源。

DESCRIPTION (provided by applicant): 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 of haplotypes in twelve relevant candidate genes. These genes will include glutamatecysteine ligase (GCLC [catalytic subunit] and GCLM[regulatory subunit]), folate-metabolizing genes (reduced folate 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.