Molecular Prognostic Indicators in Liver Cirrhosis and Cancer

肝细胞癌（HCC）的发病率和死亡率（5年生存率<12%）不断增加，这突出表明迫切需要改善对这种致命肿瘤的预测和预防。HCC由B型肝炎病毒（HBV）、丙型肝炎病毒（HCV）、酒精或非酒精性脂肪性肝病（NAFLD）引起的晚期纤维化发展而来。先前在HCV相关肝硬化中鉴定和验证的间质性肝硬化中的186个基因预后特征有望识别具有最高HCC风险的患者并为HCC预防靶点提供线索。目前尚不清楚这种特征是否也是其他HCC病因的预后。此外，该签名尚未被改编为临床适用的测试。我们的长期目标是为各种病因引起的全球肝硬化人群开发临床适用的预后生物标志物，以实现更有效，个性化的HCC监测和预防。本研究的目的是建立186基因标记在非HCV病因学中的预后相关性，鉴定病因学特异性分子预后因素，实施和完善标记作为临床适用的检测方法，并开发用于预后生物标志物评估的基因组数据库。我们的中心假设是，186个基因的签名是普遍的预后与病因无关，也有互补的，病因特异性的预后指标。我们将测试这些假设，并通过以下相互关联的具体目标来解决未满足的需求：1。在非HCV病因的晚期肝病患者中建立HCC风险和不良预后的基因特征我们将对间质硬化肝组织（905例肝硬化和1025例受HBV、HCV、酒精或NAFLD影响的HCC病例）进行全基因组表达谱分析，并验证HCC发展以及肝硬化进展和死亡的预测能力。还将使用全基因组数据集鉴定病因特异性预后基因特征。2.使用定义HCC风险的基因签名开发临床适用的预后测试。我们将在专门为临床实验室设计的数字转录本计数技术（nCounter assay，NanoString）中实现签名，并优化实验和分析方法。基于转录组测序的预测也将被评估为临床测试的潜在未来平台。3.开发一个网络资源，用于肝硬化和HCC的计算机预测生物标志物评估。我们的新数据集和现有数据集代表了全球肝硬化患者人群，将作为一个公共数据库进行组装，使用户的预后分子特征的临床实用性评估变得快速简便。

DESCRIPTION (provided by applicant): The accelerating incidence and dismal mortality of hepatocellular carcinoma (HCC) (5-yr survival <12%) highlight the urgent need to improve prediction and prevention of this deadly neoplasm. HCC develops from advanced fibrosis due to hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol, or non-alcoholic fatty liver disease (NAFLD). A 186-gene prognostic signature in stromal cirrhotic liver, previously identified and validated in HCV-related cirrhosis, holds promise to identify patients with highest HCC risk and provide clues to HCC prevention targets. It remains unknown whether this signature is also prognostic for other HCC etiologies. Moreover, the signature has not yet been adapted as a clinically applicable test. Our long-term goal is to develop clinically applicable prognostic biomarkers for the global cirrhosis population caused by variety of etiologies to enable more effective, personalized HCC surveillance and prevention. The objective here is to establish prognostic relevance of the 186-gene signature in the non-HCV etiologies, identify etiology-specific molecular prognostic factors, implement and refine the signature as a clinically applicable assay, and develop genomic database for prognostic biomarker assessment. Our central hypotheses are that the 186-gene signature is universally prognostic irrespective of etiology, and that there are also complementary, etiology-specific prognostic indicators. We will test these hypotheses and address the unmet need by the following interrelated Specific Aims: 1. Establish a gene signature of HCC risk and poor prognosis in patients with non-HCV etiologies of advanced liver disease. We will perform whole-genome expression profiling of stromal cirrhotic liver tissues (905 cirrhosis and 1025 HCC cases affected by HBV, HCV, alcohol, or NAFLD), and validate predictive capability for HCC development as well as cirrhosis progression and death. Etiology-specific prognostic gene signatures will also be identified using the whole-genome datasets. 2. Develop a clinically applicable prognostic test using gene signature that defines HCC risk. We will implement the signature in the digital transcript counting technology specifically designed for clinical lab (nCounter assay, NanoString), and optimize experimental and analytical methods. Transcriptome sequencing-based prediction will also be evaluated as a potential future platform of a clinical test. 3. Develop a web resource for in silico prognostic biomarker assessment for cirrhosis and HCC. Our new and existing datasets, representing a global cirrhosis patient population, will be assembled as a public database that enables quick and easy clinical utility assessment of a user's prognostic molecular signatures.