The Molecular Epidemiology Of Ovarian Cancer

卵巢癌的分子流行病学

• 批准号: 6806049
• 负责人: Joellen M. SCHILDKRAUT
• 金额: $ 63.81万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6806049
• 关键词: DNA damage; DNA repair; cancer risk; clinical research; disease /disorder classification; female; genetic polymorphism; genetic susceptibility; human subject; molecular oncology; neoplasm /cancer epidemiology; neoplasm /cancer genetics; ovary neoplasms; single nucleotide polymorphism

DESCRIPTION (provided by applicant): We propose a continuation of the North Carolina Ovarian Cancer study (NCOCS), a molecular epidemiologic study of primary epithelial ovarian cancer. This is a population-based, case-control study in a 48 county region of North Carolina. We will have enrolled approximately 500 invasive epithelial ovarian cancer cases by the start of the proposed study, and plan to enroll 300 additional cases. The central goal of the NCOCS is to define subsets of epithelial ovarian cancer on the basis of the molecular signatures associated with specific disease causing exposures. The proposed renewal application will focus on the role of genes in DNA damage response pathways in the development of ovarian cancer. We hypothesize that spontaneous errors of DNA synthesis during cell proliferation is induced by ovulation leading to tumor development and individual variation in the efficiency of repairing damaged DNA due to variants in genes in DNA damage response pathways may be associated with ovarian cancer risk. In addition we hypothesize somatic p53 mutations, the most common molecular alteration in ovarian cancers, may interact with variants in DNA damage and repair genes resulting in failed DNA repair. The specific aims are: 1) To continue accrual of ovarian cancer cases and controls to achieve a sample of 800 invasive ovarian cancer cases and 800 controls; 2) To examine the relationship between ovarian cancer risk and polymorphisms in DNA damage and repair genes including XRCC1, XPD, BARD1, BACH1, GADD45, and BASC. We will also examine polymorphisms in genes involved in the p53 DNA damage checkpoint including p21, MDM2, AFR, and PIG3 genes; and 3) To develop a high throughput approach to identification of single nucleotide polymorphisms (SNPs) that affect ovarian cancer susceptibility. The joint consideration of epidemiologic risk factors and molecular characteristics should enhance our understanding of the etiology of ovarian cancer. Elucidation of the role of reproductive and environmental risk factors and genetic susceptibility could facilitate identification of high-risk women who would be ideal candidates for preventive interventions.

描述(由申请人提供)：我们建议继续进行北卡罗来纳州卵巢癌研究(NCOCS)，这是一项关于原发上皮性卵巢癌的分子流行病学研究。这是一项在北卡罗来纳州48个县地区进行的以人口为基础的病例对照研究。到拟议的研究开始时，我们将登记大约500例侵袭性上皮性卵巢癌病例，并计划再登记300例。NCOCS的中心目标是根据与引起特定疾病的暴露相关的分子特征来定义上皮性卵巢癌的亚型。拟议的更新申请将集中在DNA损伤反应通路中的基因在卵巢癌发展中的作用。我们推测，细胞增殖过程中DNA合成的自发错误是由排卵引起的，从而导致肿瘤的发生，而由于DNA损伤反应通路中的基因变异而导致的DNA损伤修复效率的个体差异可能与卵巢癌的风险有关。此外，我们推测，卵巢癌中最常见的分子变化--体细胞p53突变，可能与DNA损伤和修复基因的变异相互作用，导致DNA修复失败。其具体目标是：1)继续增加卵巢癌病例和对照，以达到800例浸润性卵巢癌和800例对照的样本；2)研究DNA损伤和修复基因XRCC1、XPD、BARD1、BACH1、GADD45和BASC的多态与卵巢癌风险的关系。我们还将检测p53 DNA损伤检查点相关基因的多态性，包括p21、MDM2、AFR和PIG3基因；以及3)建立一种高通量方法来鉴定影响卵巢癌易感性的单核苷酸多态(SNPs)。流行病学危险因素和分子特征的联合考虑应提高我们对卵巢癌病因的认识。阐明生殖和环境风险因素以及遗传易感性的作用，有助于确定哪些高危妇女是预防干预的理想对象。