Proteomic, Genomic, and Longitudinal Pathways to Ovarian Cancer Biomarker Discovery

卵巢癌生物标志物发现的蛋白质组学、基因组学和纵向途径

基本信息

批准号：
9903237
负责人：
Michael Birrer
金额：
$ 57.17万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-24 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903237
关键词：
Adnexal Mass Affect Algorithms BRCA1 Mutation BRCA1 gene BRCA2 Mutation Benign Biological Assay Biological Markers Blood Blood Circulation Blood Tests Cancer Control Cancer Detection Cancer Patient Clinical Collaborations DNA DNA Sequence Alteration Detection Diagnosis Diagnostic Disease Early Detection Research Network Early Diagnosis Family Feces Foundations Genomics High Risk Woman High-Throughput Nucleotide Sequencing Incidence Label Lead Liquid substance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Massive Parallel Sequencing Measures Mutation Mutation Detection Nucleic Acids Ovary Pathway interactions Patients Pelvis Peripheral Persons Plasma Plasma Proteins Population Population Heterogeneity Postmenopause Probability Proteins Proteomics Recording of previous events Research Sampling Screening for Ovarian Cancer Screening for cancer Sensitivity and Specificity Serous Signal Transduction Source Specificity Sputum Target Populations Techniques Technology Testing Time Tissues Uncertainty Urine Validation Variant Woman age group assay development base biobank biomarker discovery biomarker panel cancer biomarkers cancer cell cancer invasiveness candidate marker case control cervicovaginal clinical application cohort design genomic biomarker improved outcome macromolecule mortality next generation sequencing novel strategies ovarian neoplasm pre-clinical programs protein biomarkers public health relevance screening tumor DNA vaginal fluid

项目摘要

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.

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，这些人群包括因卵巢癌而处于高风险的女性。家族史和/或家族中是否存在 BRCA1 或 BRCA2 突变，以及所有绝经后女性。该年龄组的疾病发病率最高，且该测试对早期疾病的敏感性很高。特异性，以便每次真阳性检测都不会出现假阳性检测，具体目标是 1) 通过对大型队列筛选研究获得的系列血浆进行纵向蛋白质组学分析，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进行验证。通过变化点分析和按最早变化点排序，4) 对前 50 个候选蛋白质构建靶向质谱分析，并在临床检测前的病例和对照中的纵向血浆中测量这些候选蛋白，其中病例和对照来自卵巢癌筛选试验，4) 通过估计候选者显着高于基线的变化点来确定哪些候选者具有最早的敏感性，以及 5) 从恶性和良性女性宫颈阴道液的基因组分析中发现高概率候选 DNA 突变生物标志物盆腔肿块，6) 在来自病例和良性对照的独立验证 CVF 样本集中验证 DNA 突变候选者，进一步细化和测试蛋白质组和基因组生物标志物及其组合，以确定最佳组和组合。计划在更大规模的筛选研究的生物样本库中早期检测卵巢癌生物标志物的分类器，但不属于本申请的范围。