Proteomic, Genomic, and Longitudinal Pathways 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，以及所有绝经后女性。这是发病率最高的年龄组。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）通过对从大群组的筛选研究获得的系列血浆进行纵向蛋白质组学分析来发现高概率的候选生物标志物，3）优先考虑候选蛋白质生物标志物，以通过变点分析进行验证，并通过最早的变点进行排序，四、构建针对前50名候选蛋白质的靶向质谱测定，并在之前的情况下在纵向血浆中测量这些候选蛋白质。临床检测和对照，其中病例和对照来自卵巢癌筛查试验，4）通过估计候选物显著高于基线的变化点来确定哪些候选物具有最早的敏感性，和5）从患有恶性和良性盆腔肿块的妇女的宫颈阴道液的基因组分析中发现高概率的候选DNA突变生物标志物，6）在来自病例和良性对照的CVF的独立验证样品组中验证DNA突变候选物。计划进一步完善和测试蛋白质组学和基因组生物标志物及其组合，以鉴定更大规模筛选研究的生物储存库中早期检测卵巢癌生物标志物的最佳组和分类器，但这超出了本申请的范围。

 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.