Proteomic, Genomic, and Longitudinal Pathways 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，以及所有绝经后妇女。这是疾病发病率最高的年龄段。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)通过对从大队列筛选研究中获得的连续血浆的纵向蛋白质组学分析来发现高概率候选生物标记物，3)通过变点分析和按最早变化点对候选蛋白质生物标记物进行排序来确定候选蛋白质生物标记物的优先顺序，4)针对前50个候选蛋白质构建目标质谱学分析，并在临床检测之前的病例和对照中测量这些候选的纵向血浆中的这些候选，其中病例和对照来自卵巢癌筛查试验，4)通过估计候选显著高于基线的变化点来确定哪些候选具有最早的敏感性，5)从恶性和良性盆腔肿块患者宫颈阴道液的基因组分析中发现高概率DNA突变生物标志物，6)在病例和良性对照的CVF的独立验证样本集中验证DNA突变候选基因。计划进一步改进和测试蛋白质组和基因组生物标记物及其组合，以在大规模筛查研究的生物信息库中确定早期检测卵巢癌生物标记物的最佳组合和分类器，但不在本申请的范围内。

 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 BRCA1 or BRCA2 mutation within the family, and all postmenopausal women. This is the age group 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 longitudinal proteomic analysis of serial plasma obtained from screening studies of large cohorts, 3) prioritize candidate protein biomarkers for verification by change-point analysis and ranking by earliest change-point, 4) construct targeted mass spectrometric assays for the top 50 protein candidates and measure these candidates in longitudinal plasma in cases prior to clinical detection and in controls, where cases and controls are from an ovarian cancer screening trial, 4) determine which candidates have earliest sensitivity by estimating the change-point at which the candidate rises significantly above baseline, and 5) discover high probability candidate DNA mutational biomarkers from genomic analysis of cervico-vaginal fluid in women with malignant and benign pelvic masses, 6) validate DNA mutational candidates in an independent validation sample set of CVF from cases and benign controls. Further refinement and testing of proteomic and genomic biomarkers and their combination to identify the best panel and classifier of early detection ovarian cancer biomarkers in the biorepositories of larger scale screening studies is planned but is outside the scope of this application.