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发现卵巢癌的血液测试，通过对目标人群的定期测试来降低卵巢癌死亡率。最初，这些人群将包括因家族史和/或家庭内存在BRCA1或BRCA2突变而处于高危状态的妇女，以及所有发病率最高的绝经后妇女。该检测要求对早期疾病有很高的敏感度和非常高的特异度，因此每一次真阳性检测都不会出现假阳性检测。具体目的是1)通过对来自三个来源的生物体液的蛋白质组学分析来发现高概率候选生物标记物，a)来自良性和恶性卵巢疾病的卵巢囊液，b)来自新鲜切片的正常和恶性组织的条件培养液，以及c)来自表观复制模型输卵管系统的条件培养液，2)使用由来自卵巢组织(分泌体)的分泌蛋白的综合列表过滤的正常输卵管、正常卵巢和卵巢恶性组织裂解物的基因组分析，从基因组分析中发现高概率候选生物标记物，3)优先选择候选生物标记物用于通过对卵巢癌发病机制的路径分析进行验证，4)建立前50名候选人的质谱学分析方法，并测量100例患者和100名良性对照的血浆、临床检测前病例的纵向血浆和卵巢癌筛查试验的对照血浆中的这些候选人，以及5)通过估计候选人显著高于基线的变化点(如果有)来确定哪些候选人具有最早的敏感性。这五个最佳候选者将组成一个生物标志物小组，在本申请范围之外，在更大规模的筛选研究的生物信息库中进行进一步的测试和提炼。

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.