Proteomic Genetic and Longitudinal Paths to Ovarian Cancer Biomarker Discovery

描述（由申请人提供）：该应用程序的广泛，长期目标是发现一种用于早期检测卵巢癌的血液检测，通过定期检测目标人群，降低卵巢癌死亡率。最初，这些人群将包括由于家族史和/或家族内存在BRCA 1或BRCA 2突变而处于高风险的女性，以及疾病发生率最高的所有绝经后女性。该测试需要对早期疾病的高灵敏度和非常高的特异性，使得对于每个真阳性测试将发生很少的假阳性测试。具体目的是1）通过对来自三个来源的生物流体进行蛋白质组学分析来发现高概率的候选生物标志物，a）来自良性和恶性卵巢疾病的卵巢囊肿液，B）来自新鲜切片的洗涤的正常和恶性组织的条件培养基，和c）来自表型模型输卵管系统的条件培养基，2）从使用正常输卵管，正常卵巢，以及通过来自卵巢组织的分泌蛋白质的综合列表过滤的卵巢恶性组织裂解物（分泌组），3）通过分析来自卵巢癌发病机制的途径来区分用于验证的候选生物标志物的优先级，4）为前50名候选者构建质谱测定，并在来自100个病例和100个良性对照的血浆中，以及在临床检测之前的病例中的纵向血浆中，以及在来自卵巢癌筛查试验的对照中，测量这些候选者，以及5）通过估计候选者显著地上升到基线以上的变化点（如果有的话）来确定哪些候选者具有最早的敏感性。五个最佳候选者将形成生物标志物组，用于在本申请范围之外的更大规模筛选研究的生物储存库中进行进一步测试和改进。

DESCRIPTION (provided by applicant): The application's broad, long-term objectives are to discover a blood test for early detection of ovarian cancer that will reduce ovarian cancer mortality through regular testing of targeted populations. Initially these populations would include women at high risk due to family history and/or presence of a BRCA1or BRCA2 mutation within the family, and all postmenopausal women where the incidence of disease is highest. The test requires high sensitivity for early stage disease and very high specificity so that few false positive tests will occur for each true positive test. The specific aims are 1) to discover high probability candidate biomarkers through proteomic analysis of biofluids from three sources a) ovarian cyst fluid from benign and malignant ovarian disease, b) conditioned media from fresh sliced washed normal and malignant tissue, and c) conditioned media from phenocopy model fallopian tube systems, 2) discover high probability candidate biomarkers from genomic analysis using Affymetrix arrays of normal fallopian tube, normal ovarian, and ovarian malignant tissue lysate filtered by a comprehensive list of secreted proteins from ovarian tissue (secretome), 3) prioritize candidate biomarkers for verification by analysis of pathways from ovarian cancer pathogenesis, 4) construct mass spectrometric assays for the top 50 candidates and measure these candidates in plasma from 100 cases and 100 benign controls, and in longitudinal plasma in cases prior to clinical detection, and in controls from an ovarian cancer screening trial, and 5) determine which candidates have earliest sensitivity by estimating the change-point (if any) at which the candidate rises significantly above baseline. The five best candidates will form a biomarker panel for further testing and refinement, outside the scope of this application, in the biorepositories of larger scale screening studies.