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

描述（由申请人提供）：我们将进行一项全面的分子流行病学调查，研究NF-κ B通路的遗传变异在卵巢癌病因学中的作用。大量证据表明，炎症，细胞凋亡和免疫反应过程与卵巢癌发生有关。NF-κ B是这些过程的核心转录因子家族，其调节许多基因的表达。我们假设NF-κ B亚基或NF-κ B抑制剂和激活剂的遗传变异可能会改变NF-κ B的活性，并导致炎症、凋亡和免疫反应的个体间差异。我们将使用一个三阶段的研究设计来检查这种遗传变异（具体来说，260个NF-κ B相关基因中超过3,000个信息多态性）是否与卵巢癌的风险相关。这项工作的前两个阶段将包括对在罗切斯特的马约诊所和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分裂样本组序贯分析，包括1,700例病例和1,800例频率匹配的对照。我们研究的第三阶段包括使用澳大利亚昆士兰州医学研究所和英国剑桥大学正在进行的研究的数据对大约50种多态性进行外部验证。这种基于路径的、多阶段的、以联系不平衡为重点的综合性方法将流行病学方法学最前沿的设计要素纳入其中。总之，本研究将提供极好的统计功效来检测中度增加的比值比。我们的目标是从编码NF-κ B亚单位和调节分子的260个候选基因中鉴定与卵巢癌最相关的基因子集。在研究的每个阶段显示重复关联的基因和遗传变异的“候选名单”将由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.