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

描述（由申请人提供）：大量的数据积累表明雌激素与乳腺癌（BC）的发展有关。儿茶酚雌激素通路一直是BC研究的焦点，因为某些儿茶酚雌激素代谢物具有遗传毒性。也就是说，这些雌激素代谢物能够形成DNA加合物，这种加合物可能导致DNA突变，其方式类似于苯（一种已知的致癌物质）。GER测定提供了尿液中与DNA碱基对结合的雌激素代谢物与未结合的雌激素代谢物的比例信息，从而量化了雌激素代谢物从DNA中去除碱基对的程度。我们的实验室同事在两项小规模研究中观察到，与低风险的健康对照相比，乳腺癌患者和高风险的健康女性的GER更高。虽然这些研究支持BC的发展受GER影响的假设，但这些数据需要在大型前瞻性研究中得到验证。方法：我们建议在WHI队列中进行一项巢式病例对照研究，使用360例BC病例和360例匹配对照者在诊断前收集的尿液样本，以检查BC与GER相关的风险（特定目标1），并调查饮食摄入是否与GER相关（特定目标2）。我们的次要目标包括探索GER、饮食因素和BC通路中效应调节剂的存在（次要目标1），并检查雌激素代谢物的减少是否与目前包含GER的38种代谢物一样可预测BC风险（次要目标2）。摘要：这项拟议的研究将是第一个使用前瞻性收集的样本来检查与这种新型雌激素生物标志物相关的BC风险的研究。利用来自一流研究（如WHI）的现有数据，为解决GER周围的研究差距提供了一种有效方法。我们经验丰富的多学科研究团队非常适合开展这项重要的研究项目。从该提案中产生的数据可以为GER生物标志物在乳腺癌中的应用提供信息。

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.