Modifiable Risk Factors and Gene/Environment interactions in Ovarian Cancer

通过确定可改变的暴露或实用的化学预防剂来进行卵巢癌的一级预防一直是该疾病流行病学研究的一个难以捉摸的目标，部分原因是所确定的风险因素相对较弱或在研究中不一致。该项目提出了两种策略来解决这些限制。为了解释为什么某些风险因素的影响是适度的，可能有必要确定基因-环境相互作用，风险因素之间的修饰，或卵巢癌组织学类型的变化。为了解决一致性问题，拥有不同数据集的研究人员在数据分析过程中应更密切地合作，以确保使用暴露和混杂因素的共同定义。病例对照研究和队列研究之间的一致性将提供关于风险因素的特别令人信服的证据。对于这项提议，研究人员将利用两项大型研究（护士健康研究队列和新英格兰卵巢癌病例对照研究）的现有数据和生物标本，联合起来解决以下假设。首先，通过慢性炎症产生的自由基损伤，生殖器暴露于滑石粉会增加卵巢癌的风险;并且这种关联可能会被解毒途径中的基因变体所改变。其次，通过多种机制，抗炎药可以降低卵巢癌的风险;并且这种关联可能被代谢途径中的基因变体所修饰。第三，通过增加类固醇的产生，咖啡因的摄入可能会影响卵巢癌的风险差异绝经状态;和相关性可能会进一步修改胆固醇消费，吸烟，激素的使用，或咖啡因代谢途径的基因变异。最后，类胡萝卜素通过其抑制活性氧或影响生长途径的能力，可以降低卵巢癌的风险;但是，有必要对导致研究之间异质性的因素进行系统研究，并检查其他类型的抗氧化剂的作用，如 类黄酮将通过对所有上皮类型组合和以下类别进行分析来评估组织学变异：浆液浸润性、浆液边界性、粘液性、类浆液性和透明细胞以及其他/未分化类型。在本项目中评估的常见生活方式暴露，而不是更强的风险因素，如怀孕史，可能更容易改变。澄清它们的作用将允许更强有力的公共卫生建议，并可能减少卵巢癌的发生。

The primary prevention of ovarian cancer through the identification of modifiable exposures or practical chemopreventive agents has been an elusive goal of epidemiologic studies of the disease, partly because the risk factors identified are relatively weak or inconsistent among studies. This project proposes two strategies to address these limitations. To explain why certain risk factors are modest in effect, it may be necessary to identify gene-environment interactions, modification between risk factors, or variation by histologic type of ovarian cancer. To address the issue of consistency, researchers with separate data sets should work more closely together during data analysis to be certain that common definitions of exposures and confounders are used. Consistency between case-control and cohort studies would provide especially compelling evidence about risk factors. For this proposal, researchers working with existing data and biologic specimens from two large studies, the Nurses' Health Study Cohort and a New England based case-control study of ovarian cancer, will join forces to address the following hypotheses. First, by free radical damage generated from chronic inflammation, genital exposure to talc increases risk for ovarian cancer; and the association may be modified by variants of genes in detoxification pathways. Second, by a variety of mechanisms, anti-inflammatory drugs may reduce the risk for ovarian cancer; and the association may be modified by variants of genes in metabolic pathways. Third, by enhancing steroid production, caffeine consumption may affect ovarian cancer risk differentially by menopausal status; and the association may be further modified by cholesterol consumption, smoking, hormonal use, or variants of genes in caffeine metabolism pathways. Finally, by their ability to scavenge reactive oxygen species or affect growth pathways, carotenoids may reduce risk for ovarian cancer; but a systematic investigation of factors contributing to heterogeneity between studies is necessary as well as an examination of the effect of other types of antioxidants such as the flavonoids. Histologic variation will be assessed by conducting analyses for all epithelial types combined and the following categories: serous invasive, serous borderline, mucinous, endometrioid and clear cell, and other/undifferentiated types. The common lifestyle exposures to be assessed in this project, as opposed to stronger risk factors like pregnancy history, may be more amenable to change. Clarifying their role would permit stronger public health advice and potentially decrease ovarian cancer occurrence.