Proteomics and Biomarkers for Hepatocellular Cancer

肝细胞癌的蛋白质组学和生物标志物

• 批准号: 6803571
• 负责人: Nezam Hassan Afdahl
• 金额: $ 17万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-25 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803571
• 关键词: biomarker; cancer registry /resource; clinical research; disease /disorder proneness /risk; early diagnosis; enzyme linked immunosorbent assay; fibrosis; hepatitis C; hepatitis C virus; hepatocellular carcinoma; high throughput technology; human tissue; informatics; liver cirrhosis; longitudinal human study; mass spectrometry; matrix assisted laser desorption ionization; molecular weight; neoplasm /cancer diagnosis; protein quantitation /detection; protein sequence; proteomics; serum

DESCRIPTION (provided by applicant): Hepatitis C (HCV) is the commonest cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) in the United States. HCC occurs primarily in patients with advanced fibrosis and cirrhosis from HCV. Current screening techniques involve the use of serum alfafetoprotein and liver imaging with ultrasound performed in high risk patients on a 3 to 6 monthly basis. Early detection can improve outcomes with liver transplantation and perhaps non-surgical therapies. However screening is not very effective and many patients present with large tumors or multifocal HCC with a median survival of only 6 months. There is a definite clinical need for better non-invasive biomarkers for HCC which can lead to early detection and treatment. The specific aims of this exploratory R21 proposal are to utilize a proteomic approach to identify novel biomarkers for HCC and then evaluate these biomarkers in a cohort of patients with HCV at high risk for HCC. The initial step will be identification of a matching group of patients with a high risk of HCC and those who have developed HCC during the prospective COPILOT study. The COPILOT study provides a large cohort of patients with HCV and cirrhosis who are randomized to treatment with either low dose PEGylated interferon alfa 2b or colchicine and are followed for 4 years with rigorous clinical screening for HCC. The study is in year 2 and the incidence of HCC is approximately 5%. Serum from these patients prior to and after the development of HCC is stored and will be utilized for proteomic studies. Tissue from normal liver and HCC is available from these patients who have undergone liver transplant. A control disease serum bank from patients with HCC unrelated to HCV is also available at BIDMC. The serum and tissue will be examined by proteomics for identification of novel biomarkers using SELDI-TOF mass spectrometry. Careful clinical characterization and matching will assist in the bioinformatic approach necessary to identify candidate biomarkers. Novel proteins and peptide biomarkers will be sequenced and identified and an ELISA will be developed for any promising candidate biomarkers. The candidate biomarker ELISA will then be validated in the large HCV serum bank at BIDMC of patients with all stages of HCV and those in the COPILOT trial. These studies may lead to identification of more specific and sensitive biomarkers for HCC in HCV which can then be validated further in prospective clinical trials.

描述（由申请人提供）：丙型肝炎（HCV）是美国慢性肝炎、肝硬化和肝细胞癌（HCC）最常见的病因。HCC主要发生在HCV引起的晚期纤维化和肝硬化患者中。目前的筛查技术包括对高危患者每3至6个月进行一次血清阿尔法蛋白和肝脏超声成像。早期发现可以改善肝移植和非手术治疗的结果。然而，筛查不是很有效，许多患者出现大肿瘤或多灶性HCC，中位生存期仅为6个月。临床明确需要更好的非侵入性HCC生物标志物，以便早期发现和治疗。这项探索性R21提案的具体目的是利用蛋白质组学方法鉴定HCC的新生物标志物，然后在HCC高风险的HCV患者队列中评估这些生物标志物。第一步将是确定一组匹配的HCC高风险患者和在前瞻性COPILOT研究期间已发生HCC的患者。COPILOT研究提供了一个大型HCV和肝硬化患者队列，这些患者随机接受低剂量聚乙二醇化干扰素α 2b或秋水仙碱治疗，并进行了为期4年的严格的HCC临床筛查。该研究为第2年，HCC发生率约为5%。储存这些患者发生HCC前后的血清，用于蛋白质组学研究。这些接受过肝移植的患者可以获得正常肝脏和HCC的组织。BIDMC还提供了与HCV无关的HCC患者的对照疾病血清库。血清和组织将通过蛋白质组学检测，使用SELDI-TOF质谱法鉴定新的生物标志物。仔细的临床特征和匹配将有助于确定候选生物标志物所需的生物信息学方法。将对新的蛋白质和肽生物标记物进行测序和鉴定，并为任何有希望的候选生物标记物开发ELISA。候选生物标志物ELISA将在BIDMC所有阶段HCV患者和COPILOT试验中的大型HCV血清库中进行验证。这些研究可能会导致HCV中HCC更特异性和敏感性的生物标志物的鉴定，然后可以在前瞻性临床试验中进一步验证。