Molecular Prognostic Indicators in Liver Cirrhosis and Cancer

描述（由申请人提供）：肝细胞癌（HCC）的发病率不断上升，死亡率低（5年生存率<12%），这表明迫切需要改进对这种致命肿瘤的预测和预防。HCC由乙型肝炎病毒（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。一项由186个基因组成的间质性肝硬化预后特征，先前在hcv相关肝硬化中被发现并验证，有望识别HCC风险最高的患者，并为HCC预防目标提供线索。目前尚不清楚这一特征是否也预示着其他HCC病因。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全球各种病因导致的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。目的是建立186基因标记在非hcv病因中的预后相关性，确定病因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基因的特征是普遍的预后，而不考虑病因，也有补充的，病因特异性的预后指标。我们将通过以下相互关联的具体目标来检验这些假设并解决未满足的需求：在非hcv病因的晚期肝病患者中建立HCC风险和预后不良的基因标记。我们将对间质性肝硬化肝组织（905例肝硬化和1025例受HBV、HCV、酒精或NAFLD影响的HCC）进行全基因组表达谱分析，并验证HCC发展、肝硬化进展和死亡的预测能力。病因特异性预后基因特征也将使用全基因组数据集进行鉴定。2. 开发一种临床适用的预后测试，使用基因标记来定义HCC风险。我们将在专门为临床实验室设计的数字转录计数技术（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潜在的未来临床测试平台。3. 开发一个用于肝硬化和肝细胞癌的计算机预后生物标志物评估的网络资源。我们的新数据集和现有数据集，代表了全球肝硬化患者群体，将被组装成一个公共数据库，使快速和简单的临床效用评估用户的预后分子特征。

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.