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

NF-kappaB 通路的遗传变异与卵巢癌病因学

• 批准号: 8291440
• 负责人: ELLEN L. GOODE
• 金额: $ 1.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291440
• 关键词: Address; Apoptosis; Apoptotic; Australia; Cancer Etiology; Candidate Disease Gene; Clinic; Collection; Data; Development; Elements; Environment; Epidemiologic Studies; Epidemiology; Evaluation; Family; Frequencies; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Goals; Immune response; Immunity; Immunologics; Individual; Individual Differences; Inflammation; Inflammatory; Inherited; Institutes; Lead; Link; Linkage Disequilibrium; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Medical Research; Methodology; Molecular; Morbidity - disease rate; NF-kappa B; National Cancer Institute; Natural Immunity; Nuclear; Odds Ratio; Ovarian; Participant; Pathway interactions; Phase; Play; Population Study; Preventive; Process; Progress Review Group; Property; Queensland; Recruitment Activity; Research Design; Risk; Role; Sampling; Screening procedure; Signaling Molecule; Single Nucleotide Polymorphism; Testing; Therapeutic; Therapeutic Studies; Universities; Validation; Variant; Woman; Work; adaptive immunity; base; cancer risk; carcinogenesis; design; genetic variant; inhibitor/antagonist; mortality; novel; ovarian neoplasm; transcription factor

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.

描述（由申请人提供）：我们将对NF-KAPPAB途径在卵巢癌病因中发挥作用的遗传变异作用进行全面的分子流行病学研究。大量证据表明，炎症，凋亡和免疫反应过程与卵巢癌发生有关。 NF-kappab是这些过程中核心的转录因子家族，这些过程调节了许多基因的表达。我们假设NF-kappab亚基或NF-kappab抑制剂和激活剂的遗传变异可能会改变NF-kappab的活性，并导致炎症，凋亡和免疫反应的个体间差异。我们将使用三相研究设计来检查这种遗传变异（特别是在260个NF-kappab相关基因中超过3,000种信息性多态性）是否与患卵巢癌的风险有关。这项工作的前两个阶段将包括对正在进行的卵巢癌研究的参与者进行的分式样本群顺序分析，该研究人员在北卡罗来纳州罗切斯特的梅奥诊所和北卡罗来纳州达勒姆市的杜克大学，包括1,700例和1,800例频率匹配的对照组。我们研究的第三阶段包括使用昆士兰医学研究所（澳大利亚昆士兰医学研究所和英国剑桥大学）正在进行的研究中对大约50种多态性的外部验证。这种基于途径的综合途径，以链接不平衡为中心的方法将设计元素纳入了流行病学方法论的最前沿。总的来说，这项研究将提供出色的统计能力，以检测中度增加的优势比。我们的目标是确定来自编码NF-kappab亚基和调节分子的260个候选基因中与卵巢癌最相关的基因子集。然后，在整个研究的每个阶段，都显示出复制关联的基因和遗传变异的“入围名单”，然后由我们的跨学科团队转变为下游功能分析，以识别未来的预防和治疗策略。

项目成果

Assessment of genotype imputation methods.

• DOI: 10.1186/1753-6561-3-s7-s5
• 发表时间: 2009-12-15
• 期刊: BMC proceedings
• 作者: Biernacka JM;Tang R;Li J;McDonnell SK;Rabe KG;Sinnwell JP;Rider DN;de Andrade M;Goode EL;Fridley BL
• 通讯作者: Fridley BL

No association between a candidate TCF7L2 variant and risk of breast or ovarian cancer.

• DOI: 10.1186/1471-2407-9-312
• 发表时间: 2009-09-04
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Goode EL;Szabo C;Prokunina-Olsson L;Vierkant RA;Fredericksen ZS;Collins FS;White KL;Schmidt M;Fridley BL;Couch FJ
• 通讯作者: Couch FJ

Single versus multiple imputation for genotypic data.

• DOI: 10.1186/1753-6561-3-s7-s7
• 发表时间: 2009-12-15
• 期刊: BMC proceedings
• 作者: Fridley BL;McDonnell SK;Rabe KG;Tang R;Biernacka JM;Sinnwell JP;Rider DN;Goode EL
• 通讯作者: Goode EL