Blood metabolite profiles and risk of developing endometrial cancer

项目摘要 癌症是美国的主要死因，三分之一的诊断归因于可改变的风险 包括肥胖和不良饮食。了解这些危险因素在癌症发展中的作用， 这对提供适当的癌症预防公共卫生指导至关重要。 乳腺癌仍然是美国女性中发病率最高的癌症， 子宫内膜癌的发病率预计在未来十年将急剧上升。流行病学、临床 实验室证据表明，饮食可能与乳腺癌和子宫内膜癌的预防有关， 虽然证据基础缺乏一致性，可能是由于不精确的饮食措施，以及未能 解释了可能因肿瘤亚型而异的关联。此外，子宫内膜癌尤其是 肥胖驱动的，但潜在的机制还没有得到充分的特点。 需要更好的饮食客观指标，包括饮食生物标志物，可用于改善 膳食评估代谢组学是分子流行病学中的一项新兴技术， 用于同时测量数百至数千种循环代谢物，其中200多种 最近与个人的饮食和/或肥胖有关。此外，代谢组学可用于 突出了与疾病相关生物学机制。这项新技术正在迅速发展， 在流行病学的背景下应用它还有很多工作要做。 为了解决这一未满足的需求，我建议应用代谢组学来了解饮食与代谢的关系。 肥胖与女性癌症我将首先量化循环代谢物和习惯性 在一项喂养研究中，使用金标准饮食（称重食物）， 绝经后妇女，以开发客观的饮食生物标志物。这项工作对于正确的 在随后的癌症研究中可能观察到的任何饮食相关代谢物信号的解释。接下来我 将测量诊断前循环饮食相关代谢物和雌激素受体之间的关联， 阴性（ER-）乳腺癌使用巢式病例对照数据从三个前瞻性队列。ER-乳腺癌 是罕见的，侵略性的，未被充分研究的因此，病因学知之甚少，包括潜在的 饮食风险因素。最后，我将确定诊断前循环代谢物是否与 子宫内膜癌发病率及其与饮食或肥胖的关系 前瞻性队列。没有研究探索子宫内膜癌的代谢物特征及其与 肥胖症和饮食使用的数据来自美国的前瞻性研究。这些研究可能会揭示未知的 乳腺癌和子宫内膜癌病因学中涉及的代谢途径，也可能适用于 其他肥胖导致的癌症，并确定开发和评估靶向癌症的关键途径 预防干预。

PROJECT SUMMARY Cancer is a leading cause of death in the United States, with a third of diagnoses attributed to modifiable risk factors including obesity and poor diet. Understanding the role of these risk factors in cancer development is crucial for the provision of appropriate public health guidance for cancer prevention. Breast cancer remains the highest incidence cancer among women in the United States, and incidence rates for endometrial cancer are projected to dramatically increase over the next decade. Epidemiological, clinical and laboratory evidence suggests that diet may be relevant for breast and endometrial cancer prevention, although the evidence base lacks consistency, perhaps owing to imprecise dietary measures, and a failure to account for associations that may vary by tumor subtype. Furthermore, endometrial cancer is especially obesity-driven, but the underlying mechanisms have yet to be fully characterized. There is a need for better objective measures of diet, including dietary biomarkers, that can be used to improve dietary assessment. Metabolomics is a novel and emerging technology in molecular epidemiology that can be used to measure hundreds to thousands of circulating metabolites simultaneously, more than 200 of which have been recently linked to an individual’s diet and/or adiposity. Furthermore, metabolomics can be used to highlight biological mechanisms of interest in relation to disease. This novel technology is advancing rapidly, and much work is yet to be done in applying it in an epidemiologic context. To address this unmet need, I propose to apply metabolomics to understanding the relationships of diet and adiposity with female cancers. I will first quantify the relationship between circulating metabolites and habitually consumed foods in a feeding study with a gold-standard measure of diet (weighed food) among postmenopausal women in order to develop objective dietary biomarkers. Such work is critical for correct interpretation of any diet-related metabolite signals that may be observed in subsequent cancer studies. Next, I will measure the association between pre-diagnostic circulating diet-related metabolites and estrogen receptor- negative (ER-) breast cancer using nested case-control data from three prospective cohorts. ER- breast cancer is rare, aggressive and understudied. Consequently, the etiology is poorly understood, including potential dietary risk factors. Finally, I will determine whether pre-diagnostic circulating metabolites are associated with incident endometrial cancer, and their relation to diet or adiposity using nested case-control data from four prospective cohorts. No studies have explored metabolite signatures of endometrial cancer and their relation to adiposity and diet using data from US-based prospective studies. These studies may uncover unknown metabolic pathways involved in the etiology of breast and endometrial cancer that may also be applicable to other obesity-driven cancers, and identify key pathways for developing and evaluating targeted cancer prevention interventions.