Dietary and Hormonal Determinants of Cancer in Women

描述(由申请者提供)：该计划项目的总体长期目标是确定乳腺癌(项目1)、结直肠癌(项目2)和卵巢癌(项目3)女性癌症风险的新的饮食、激素和基因决定因素，最终目的是找到预防和提高存活率的方法。问卷数据和生物标记物的结合，加上长期的随访，提供了进一步了解时间进程以及癌症发展机制的机会。为了实现这些目标，我们将与 A)前瞻性收集关于饮食、体重增加、体力活动、止痛剂使用和其他行为的数据； B)预期采集的血液中的营养物质和激素水平；以及 C)来自存档DNA和组织块的基因信息；与乳腺癌、结直肠癌和卵巢癌的发病率有关。 此外，第四个项目将改进多点Logistic回归的方法，并将利用先前的饮食验证研究和新的饮食验证研究，解决涉及重复测量与癌症风险有关的营养物质的方法学问题。该项目还将处理因果推断和关联建模，以及单倍型估计和单倍型-环境相互作用中的统计问题。需要采取更多的后续行动，以确定足够数量的案例，以处理每个项目中概述的假设。 该方案项目基于护士健康研究队列，包括121,700名妇女，她们在1976年登记时年龄在30岁到55岁之间。该方案项目是更新问卷数据和确认所发生的疾病的中心资源，这些疾病是解决癌症和其他重大慢性病发病率的许多相关赠款所必需的。因此，通过资助计划项目中的核心A和B，我们保持对队列的跟踪和对发生的癌症和死亡的及时确认。核心C负责样本处理和基因分析，核心D负责领导和数据分析。该计划项目还有助于支持我们的生物样本库。通过这次续签申请，我们获得了386,000美元的机构承诺，用于升级我们的冷藏设施。 我们解决了项目中的三个主要主题。每个项目都将提供一项初步评估(卵巢癌)或更深入的评估(乳腺癌和结肠癌)，以评估一种碳代谢和基因高甲基化在癌症发生中的作用。此外，对这些复杂暴露进行建模将是项目4的重点，因此优化了在其他三个项目中进行的分析。能量平衡在一生中的作用(通过体型、体力活动和胰岛素样生长因子进行评估)是这三个项目的另一个重点。炎症标志物在疾病中的作用是结肠和卵巢项目中的一个重点领域。项目4开发了数据分析的统计方法，这些方法直接应用于项目1、2和3，用于在使用重复的饮食措施时评估营养与癌症的相关性。多分类Logistic回归的方法学工作适用于每个项目，因为足够数量的病例允许评估与癌症终点亚组相关的假设(例如，导管乳腺癌与小叶乳腺癌；粘液性卵巢癌与非粘液性卵巢癌；总癌症死亡率)。此外，单倍型估计方法的发展和单倍型-环境相互作用的评估适用于每个项目，因为我们评估潜在的基因-环境相互作用。 强大的科学协同效应渗透到项目中。所有项目都基于相同的数据收集、管理、疾病跟踪和数据分析基础设施。研究人员虽然专注于自己的领域，但相互作用密切，这允许知识、想法和方法的交叉培养，并带来相当大的生产力和效率。

DESCRIPTION (provided by applicant): The overall long-term objective of this program project is to identify novel dietary, hormonal and genetic determinants of breast (Project 1), colorectal (Project 2), and ovarian (Project 3) cancer risk in women, with the ultimate aim of finding means for prevention and improved survival. The combination of questionnaire-derived data and biomarkers, coupled with the long-term follow-up, affords the opportunity to further understand of the time course, as well as mechanisms of cancer development. To achieve these objectives, we will relate a) Prospectively collected data on diet, weight gain, physical activity, analgesic use, and other behaviors; b) Nutrient and hormone levels in prospectively collected blood; and c) Genotypic information from archived DNA and tissue blocks; to incidence of breast, colorectal, and ovarian cancers. In addition, a fourth project will refine methods for polychotomous logistic regression and, using both a previous diet validation study and a new diet validation study, will address methodologic issues involving repeated measures of nutrients in relation to cancer risk. This project will also address causal inference and incidence modeling, as well as statistical issues in haplotype estimation and haplotype-environment interactions. Additional follow-up is required to identify adequate numbers of cases to address hypotheses outlined in each of the projects. This program project is based on the Nurses' Health Study cohort, comprising 121,700 women who were 30 to 55 years of age when enrolled in 1976. The program project serves as the central resource for updating questionnaire data and confirming incident diseases necessary for the many related grants addressing incidence of cancer and other major chronic diseases. Thus, through funding of Cores A and B in the program project, we maintain follow-up of the cohort and timely confirmation of incident cancers and deaths. Core C conducts specimen handling and genetic analysis and Core D provides leadership and data analysis. The program project also helps to support our repository of biological samples. With this renewal application, we have an institutional commitment of $386,000 to upgrade our freezer facility. We address three major themes across the projects. Each project will be providing either an initial assessment (ovarian cancer) or more in depth assessment (breast and colon cancers) of the role of one carbon metabolism and gene hypermethylation in carcinogenesis. Further, modeling these complex exposures will be a focus of Project 4, hence optimizing the analyses being conducted in the other three projects. The role of energy balance throughout life (as assessed through body size, physical activity, and IGF) is another focus of the three projects. The role of inflammatory markers in disease is an area of focus in both the colon and ovarian projects. Project 4 develops statistical approaches to data analysis that apply directly to Projects 1, 2, and 3 for evaluation of nutrient-cancer associations when using repeated measures of diet. Methodologic work on polychotomous logistic regression is applicable to each project as sufficient numbers of cases allow for evaluation of hypotheses relating to subsets of cancer endpoints (e.g., ductal vs., lobular breast cancer; mucinous vs. nonmucinous ovarian cancer; total cancer mortality). Furthermore, the development of methods for haplotype estimation and the evaluation of haplotype-environment interactions are applicable across each of the projects as we evaluate potential gene-environment interactions. Strong scientific synergy permeates the projects. All projects are based on the same infrastructure of data collection, management, disease follow-up, and data analysis. The investigators, although focusing on their own areas, interact closely, which allows cross-fertilization of knowledge, ideas and approaches, and results in considerable productivity and efficiency.