Genetic Variation in the NF-kappaB Pathway and Ovarian Cancer Etiology

描述(申请人提供)：我们将对核因子-kappaB途径的基因变异在卵巢癌病因中所起的作用进行全面的分子流行病学调查。大量证据表明，炎症、细胞凋亡和免疫反应过程与卵巢癌的发生有关。核因子-kappaB是一个转录因子家族，在这些过程中起核心作用，它调节许多基因的表达。我们推测，核因子-kappaB亚单位或核因子-kappaB抑制因子和激活剂的遗传变异可能会改变核因子-kappaB的活性，导致炎症、细胞凋亡和免疫反应的个体间差异。我们将使用三阶段研究设计来检验这种遗传变异(具体而言，260个核因子-kappaB相关基因中的3000多个信息性多态)是否与卵巢癌的风险有关。这项工作的前两个阶段将包括对在明尼苏达州罗切斯特的梅奥诊所和北卡罗来纳州达勒姆的杜克大学进行的卵巢癌研究中招募的参与者进行的分裂样本组顺序分析，包括1700个病例和1800个频率匹配的对照。我们研究的第三阶段包括使用澳大利亚昆士兰医学研究所和英国剑桥大学正在进行的研究数据对大约50个多态进行外部验证。这一以途径为基础、多阶段、以连锁不平衡为重点的综合方法结合了流行病学方法学最前沿的设计要素。总而言之，这项研究将提供极好的统计能力来检测适度增加的优势比。我们的目标是从260个编码NF-kappaB亚单位和调控分子的候选基因中确定与卵巢癌最相关的基因亚集。在研究的每个阶段，显示重复关联的基因和遗传变异的“入围名单”将被我们的跨学科团队过渡到下游功能分析，以确定未来的预防和治疗策略。

DESCRIPTION (provided by applicant): We will conduct a comprehensive molecular epidemiologic investigation of the role that genetic variation in the NF-kappaB pathway plays in ovarian cancer etiology. Substantial evidence suggests that inflammation, apoptosis, and immune response processes are linked to ovarian carcinogenesis. NF-kappaB is a family of transcription factors central to these processes which regulates the expression of numerous genes. We hypothesize that genetic variation in NF-kappaB subunits or NF-kappaB inhibitors and activators may modify the activity of NF-kappaB and lead to inter-individual differences in inflammation, apoptosis, and immune response. We will use a three-phase study design to examine whether this genetic variation (specifically, over 3,000 informative polymorphisms in 260 NF-kappaB-related genes) is associated with risk of ovarian cancer. The first two phases of this work will consist of a split-sample group sequential analysis of participants recruited in ongoing ovarian cancer studies at the Mayo Clinic in Rochester, MN and at Duke University in Durham, NC including 1,700 cases and 1,800 frequency-matched controls. The third phase of our study consists of external validation of approximately 50 polymorphisms using data from ongoing studies at the Queensland Institute of Medical Research, Australia, and the University of Cambridge, UK. This comprehensive pathway-based, multiple-phase, linkage disequilibrium-focused approach incorporates design elements at the forefront of epidemiologic methodology. In total, this study will provide excellent statistical power to detect moderately-increased odds ratios. Our goal is to identify the subset of genes which are most relevant to ovarian cancer from among 260 candidate genes encoding NF-kappaB subunits and regulatory molecules. The "shortlist" of genes and genetic variants showing replicated associations throughout each phase of the study will then be transitioned into downstream functional analysis by our transdisciplinary team for the identification of future preventive and therapeutic strategies.