Modifiable Risk Factors and Gene/Environment interactions in Ovarian Cancer

通过确定可改变的暴露或实际的化学预防剂来一级预防卵巢癌一直是该疾病流行病学研究的一个难以捉摸的目标，部分原因是确定的风险因素相对较弱或研究之间不一致。本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危险因素的影响是适度的，可能有必要确定基因-环境的相互作用，危险因素之间的修饰，或卵巢癌的组织学类型的变化。为了解决一致性问题，拥有独立数据集的研究人员应该在数据分析过程中更紧密地合作，以确保使用了暴露和混杂因素的共同定义。病例对照和队列研究之间的一致性将为风险因素提供特别令人信服的证据。在这项研究中，研究人员利用护士健康研究队列和新英格兰卵巢癌病例对照研究两项大型研究的现有数据和生物标本，将联手解决以下假设。首先，由于慢性炎症产生自由基损伤，生殖器接触滑石粉会增加患卵巢癌的风险；这种关联可能被解毒途径中基因的变异所修饰。第二，通过多种机制，抗炎药物可能降低卵巢癌的风险；这种关联可能被代谢途径中基因的变异所改变。第三，通过促进类固醇的产生，咖啡因摄入可能会影响不同绝经状态的卵巢癌风险；这种联系可能会因胆固醇摄入、吸烟、激素使用或咖啡因代谢途径中的基因变异而进一步改变。最后，通过清除活性氧或影响生长途径的能力，类胡萝卜素可能降低患卵巢癌的风险；但是，有必要对导致研究之间异质性的因素进行系统的调查，并对其他类型的抗氧化剂（如维生素a）的效果进行检查

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.