Proteomics and Biomarkers for Hepatocellular Cancer

描述(申请人提供)：丙型肝炎(丙型肝炎)是美国慢性肝炎、肝硬变和肝细胞癌最常见的病因。肝细胞癌主要发生在丙型肝炎病毒感染的晚期纤维化和肝硬变患者。目前的筛查技术包括使用血清甲胎蛋白和肝脏成像，并在高危患者中每3至6个月进行一次超声检查。及早发现可以改善肝移植的结果，或许还可以改善非手术治疗。然而，筛查并不是很有效，许多患者患有大肿瘤或多灶性肝癌，中位生存期仅为6个月。临床上确实需要更好的非侵入性肝癌标志物，以便及早发现和治疗。这个探索性的R21提案的具体目的是利用蛋白质组学的方法来识别新的肝细胞癌生物标记物，然后在一组丙型肝炎高危患者中评估这些生物标记物。最初的步骤将是确定一组匹配的肝癌高危患者和那些在前瞻性COPILOT研究期间发展为肝癌的患者。这项COPilot研究提供了一大批丙型肝炎病毒和肝硬变患者，他们被随机分配到接受小剂量聚乙二醇化干扰素α2b或秋水仙碱治疗，并接受为期4年的严格的肝细胞癌临床筛查。这项研究是在第二年进行的，肝癌的发病率约为5%。这些患者在肝细胞癌发生之前和之后的血清被储存起来，并将用于蛋白质组学研究。来自正常肝脏和肝细胞癌的组织可以从这些接受过肝移植的患者那里获得。BIDMC还提供了一个与丙型肝炎病毒无关的肝细胞癌患者的对照疾病血清库。血清和组织将通过蛋白质组学进行检测，以使用SELDI-TOF质谱仪识别新的生物标记物。仔细的临床特征和匹配将有助于识别候选生物标记物所需的生物信息学方法。将对新的蛋白质和多肽生物标记物进行测序和鉴定，并将为任何有前景的候选生物标记物开发酶联免疫吸附试验。候选生物标记物酶联免疫吸附试验将在BIDMC的大型丙型肝炎血清库中对所有阶段的丙型肝炎患者和COPILOT试验中的患者进行验证。这些研究可能导致在丙型肝炎中识别更特异和更敏感的肝细胞癌生物标志物，然后可以在前瞻性临床试验中进一步验证。

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.