Gentoxic Estrogen Ratio: A Novel Estrogen Biomarker and Breast Cancer Risk

描述（由申请人提供）：大量积累的数据表明雌激素与乳腺癌（BC）的发展有关。儿茶酚雌激素途径一直是BC研究的焦点，因为特定的儿茶酚雌激素代谢产物具有遗传毒性。也就是说，这些雌激素代谢物能够形成DNA加合物，这可能导致DNA突变的方式类似于苯，一种已知的致癌物质。格尔测定提供了与尿中DNA碱基对结合的雌激素代谢物相对于未结合的雌激素代谢物的比例的信息，从而定量雌激素代谢物从DNA中去除碱基对的程度。我们的实验室同事在2项小规模研究中观察到，与低风险健康对照组相比，BC患者和BC高风险健康女性的格尔率更高。虽然这些研究支持BC发展受格尔影响的假设，但这些数据需要在大型前瞻性研究中重复。研究方法：我们建议在WHI队列中进行巢式病例对照研究，使用360例BC病例和360例匹配对照在诊断前采集的尿液样本，以检查与格尔相关的BC风险（具体目标1），并调查饮食摄入是否与格尔相关（具体目标2）。我们的次要目的包括探索在涉及格尔、饮食因素和BC的途径中是否存在效应调节剂（次要目的1），并检查一组减少的雌激素代谢物是否与目前构成格尔的38种代谢物同样预测BC风险（次要目的2）。总结：这项拟议的研究将是第一项使用前瞻性收集的样本研究与这种新型雌激素生物标志物相关的BC风险的研究。利用来自顶级研究（如WHI）的现有数据，为解决围绕GER的研究空白提供了一种有效的方法。我们经验丰富的多学科研究团队非常适合开展这一重要的研究项目。从这一建议中产生的数据可以告知格尔生物标志物在乳腺癌中的应用。

DESCRIPTION (provided by applicant): A large accumulation of data has implicated estrogen in breast cancer (BC) development. The catechol estrogen pathway has been a focus of BC research because particular catechol estrogen metabolites are genotoxic. That is, these estrogen metabolites are capable of forming DNA adducts which may lead to DNA mutations in a manner similar to benzene, a known carcinogen. The GER assay provides information on the proportion of estrogen metabolites that are bound to DNA base pairs in the urine in relation to unbound estrogen metabolites, thereby quantifying the extent to which estrogen metabolites have removed base pairs from the DNA. Our laboratory colleagues observed in 2 small-scale studies that GER was higher in BC patients and healthy women at high risk of BC compared to low-risk, healthy controls. While these studies support the hypothesis that BC development is influenced by GER, these data require replication in a large, prospective study. Methods: We propose to conduct a nested case-control study within the WHI cohort using urine samples collected prior to diagnosis from 360 BC cases and 360 matched controls in order to examine the risk of BC associated with GER (Specific Aim 1) and investigate whether dietary intake is associated with GER (Specific Aim 2). Our secondary aims involve exploring the presence of effect modifiers in the pathway involving GER, dietary factors, and BC (Secondary Aim 1) and examine whether a reduced set of estrogen metabolites are equally predictive of BC risk as the current 38 metabolites comprising the GER (Secondary Aim 2). Summary: The proposed study would be the first study using prospectively-collected samples examining the risk of BC in relation to this novel, estrogen biomarker. Leveraging the existing data from a top-rate study, such as WHI, provides an efficient method for addressing the research gaps surrounding GER. Our experienced, multi-disciplinary research team is well suited to carry out this important research project. Data emanating from this proposal could inform on the utility of the GER biomarker in relation to breast cancer.