Proteomic Genetic and Longitudinal Paths to Ovarian Cancer Biomarker Discovery

卵巢癌生物标志物发现的蛋白质组遗传学和纵向路径

• 批准号: 8147825
• 负责人: Michael Birrer
• 金额: $ 72.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-24 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147825
• 关键词: BRCA2 Mutation; Benign; Biological Assay; Biological Markers; Blood Tests; Clinical; Conditioned Culture Media; Cyst Fluid; Detection; Disease; Family; Genetic; Genomics; High Risk Woman; Incidence; Malignant - descriptor; Malignant neoplasm of ovary; Mammalian Oviducts; Measures; Modeling; Ovarian; Ovarian Cysts; Ovarian Diseases; Ovarian Tissue; Pathogenesis; Pathway Analysis; Pathway interactions; Phenocopy; Plasma; Population; Postmenopause; Probability; Proteins; Proteomics; Recording of previous events; Screening for Ovarian Cancer; Screening procedure; Slice; Source; Specificity; Staging; System; Target Populations; Testing; Tissues; Woman; biobank; mortality

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.

描述（由申请人提供）：该申请的广泛、长期目标是发现一种用于早期检测卵巢癌的血液检测方法，通过对目标人群进行定期检测来降低卵巢癌死亡率。最初，这些人群包括因家族史和/或家族内存在 BRCA1 或 BRCA2 突变而处于高风险的女性，以及所有疾病发病率最高的绝经后女性。该测试需要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不会出现假阳性测试。具体目标是 1) 通过对三个来源的生物体液进行蛋白质组学分析，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、清洗过的正常和恶性组织的条件培养基，以及 c) 条件培养基从表型模型输卵管系统中，2) 使用 Affymetrix 阵列对正常输卵管、正常卵巢和卵巢恶性组织裂解物进行基因组分析，并通过综合列表过滤，发现高概率候选生物标志物卵巢组织的分泌蛋白（分泌组），3) 通过分析卵巢癌发病机制的途径，优先考虑候选生物标志物进行验证，4) 为前 50 个候选生物标志物构建质谱分析，并在 100 个病例和 100 个良性对照的血浆中测量这些候选生物标志物，以及在临床检测之前的病例中的纵向血浆中，以及在卵巢癌筛查试验的对照中，以及 5) 通过估计变化点（如果有）来确定哪些候选者具有最早的敏感性。候选人显着高于基线。五个最佳候选者将组成一个生物标志物小组，以便在本应用范围之外的更大规模筛选研究的生物样本库中进行进一步测试和完善。