Blood metabolite profiles and risk of developing endometrial cancer

项目总结 在美国，癌症是主要的死亡原因，三分之一的诊断归因于可改变的风险 因素包括肥胖和不良饮食。了解这些风险因素在癌症发展中的作用是 这对于为癌症预防提供适当的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，发病率 预计在未来十年内子宫内膜癌的发病率将大幅增加。流行病学、临床 实验室证据表明，饮食可能与预防乳腺癌和子宫内膜癌有关， 尽管证据基础缺乏一致性，可能是由于饮食措施不精确，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 这是由肥胖驱动的，但潜在的机制尚未完全确定。 有必要更好地客观衡量饮食，包括饮食生物标记物，可以用来改善 饮食评估。代谢组学是分子流行病学中的一项新兴技术，可以 用于同时测量数百到数千种循环代谢物，其中200多种 最近被认为与个人的饮食和/或肥胖有关。此外，代谢组学可以用来 突出与疾病相关的生物学机制。这项新技术发展迅速， 在将其应用于流行病学方面，还有很多工作要做。 为了解决这一未得到满足的需求，我建议应用代谢组学来理解饮食和饮食之间的关系 肥胖症与女性癌症。我将首先量化循环代谢物和习惯性代谢之间的关系 在喂养研究中食用的食物，其中包括黄金标准的饮食衡量标准(称重的食物) 以开发客观的饮食生物标记物。这样的工作对于正确的 解释在后续癌症研究中可能观察到的任何与饮食有关的代谢物信号。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联系- 来自三个前瞻性队列的嵌套病例对照数据用于阴性(ER-)乳腺癌。ER-乳腺癌 是罕见的，咄咄逼人的，而且研究不足的。因此，对其病因，包括潜在的病因，知之甚少。 饮食危险因素。最后，我将确定诊断前循环代谢物是否与 使用来自四个国家的嵌套病例对照数据研究子宫内膜癌及其与饮食或肥胖的关系 未来的队列。目前还没有研究探讨子宫内膜癌的代谢物特征及其与 使用来自美国前瞻性研究的数据来研究肥胖和饮食。这些研究可能会发现未知的 参与乳腺癌和子宫内膜癌病因学的代谢途径也可能适用于 其他由肥胖引起的癌症，并确定开发和评估靶向癌症的关键途径 预防干预措施。

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.