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: 6740691
• 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/6740691
• 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）的最常见原因。 HCC主要发生在HCV晚期纤维化和肝硬化的患者中。当前的筛查技术涉及在3至6个月的高风险患者中使用血清赤铁蛋白和肝脏成像，超声检查。通过肝移植和可能的非手术疗法，早期检测可以改善预后。但是，筛查不是很有效，许多患者出现大型肿瘤或多灶性HCC，中位生存期仅为6个月。对于HCC的更好的非侵入性生物标志物，有明确的临床需求，这可能会导致早期检测和治疗。该探索性R21提案的具体目的是利用蛋白质组学方法来识别HCC的新型生物标志物，然后在一系列HCV患者中评估这些生物标志物的HCV高风险HCC。最初的一步将是鉴定一组HCC高风险的匹配患者以及在前瞻性副驾驶研究中开发HCC的患者。副研究提供了大量患有HCV和肝硬化患者的队列，这些患者被随机地接受低剂量的pe乙酸干扰素Alfa 2B或秋水仙碱治疗，随后进行了4年的HCC，进行了严格的HCC临床筛查。该研究是在2年级的，HCC的发病率约为5％。在HCC发展之前和之后，这些患者的血清储存，并将用于蛋白质组学研究。从正常肝脏和HCC的组织可从这些接受肝移植的患者中获得。 BIDMC也提供了来自与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查，以使用SELDI-TOF质谱法鉴定新的生物标志物。仔细的临床表征和匹配将有助于鉴定候选生物标志物所需的生物信息学方法。新型蛋白质和肽生物标志物将被测序并鉴定，并将为任何有前途的候选生物标志物开发ELISA。然后，候选生物标志物ELISA将在BIDMC的大型HCV血清库中进行验证，该患者的所有阶段的HCV阶段和副本试验。这些研究可能导致HCV中HCC的更具体和敏感的生物标志物鉴定，然后在前瞻性临床试验中可以进一步验证。