Proteomic Genetic and Longitudinal Paths to Ovarian Cancer Biomarker Discovery

描述（由申请人提供）：该申请的广泛、长期目标是发现一种早期检测卵巢癌的血液检查方法，通过对目标人群的定期检测来降低卵巢癌的死亡率。最初，这些人群将包括由于家族史和/或家族中存在brca1或BRCA2突变而具有高风险的妇女，以及所有发病率最高的绝经后妇女。该测试要求对早期疾病具有很高的敏感性和非常高的特异性，因此每次真阳性测试都很少出现假阳性测试。具体目标是1)通过三种来源的生物液体的蛋白质组学分析发现高概率候选生物标志物a)良性和恶性卵巢疾病的卵巢囊肿液，b)新鲜切片洗过的正常和恶性组织的条件培养基，c)表型模型输卵管系统的条件培养基，2)使用正常输卵管、正常卵巢、3)优先考虑候选生物标志物，通过分析卵巢癌发病机制的途径进行验证；4)构建质谱分析，对前50名候选生物标志物进行分析，并在100例患者和100例良性对照的血浆中测量这些候选物，在临床检测前的纵向血浆中测量这些候选物，以及在卵巢癌筛查试验的对照组中测量这些候选物。5)通过估计候选者显著高于基线的变化点（如果有的话）来确定哪些候选者具有最早的敏感性。五个最佳候选将形成一个生物标志物小组，在本应用范围之外，在更大规模筛选研究的生物储存库中进行进一步的测试和改进。

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.