Molecular Prognostic Indicators in Liver Cirrhosis and Cancer

描述(由申请人提供)：肝细胞癌(肝细胞癌)的发病率和死亡率(5年存活率和死亡率为12%)的加速增长突显了改善对这种致命肿瘤的预测和预防的迫切需要。肝细胞癌是由乙肝病毒(乙肝病毒)、丙型肝炎病毒(丙型肝炎病毒)、酒精或非酒精性脂肪性肝病(NAFLD)引起的晚期纤维化。在间质肝硬变中，186个基因的预后标志，先前在丙型肝炎相关的肝硬变中被识别和验证，有希望识别出肝细胞癌风险最高的患者，并为肝细胞癌预防目标提供线索。目前尚不清楚这一信号是否也预示着其他肝细胞癌病因的预后。此外，该签名还没有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变人群开发临床适用的预后生物标志物，以实现更有效的、个性化的肝细胞癌监测和预防。本研究的目的是建立186基因标志物在非丙型肝炎病原学中的预后相关性，识别病因学特定的分子预后因素，实施和完善该标志物作为临床可应用的检测方法，并开发基因组数据库用于预后生物标志物的评估。我们的中心假设是，186基因标记是普遍的预后指标，与病因无关，而且还有补充的、病因学特定的预后指标。我们将验证这些假说，并通过以下相关的具体目标来解决尚未得到满足的需求：1.在晚期肝病的非丙型肝炎病因患者中建立肝癌风险和不良预后的基因标志。我们将对间质肝硬变组织(905例肝硬变和1025例受乙肝病毒、丙型肝炎病毒、酒精或非酒精性脂肪肝影响的肝细胞癌患者)进行全基因组表达谱分析，并验证对肝细胞癌发展以及肝硬变进展和死亡的预测能力。病因学特定的预后基因签名也将使用全基因组数据集进行识别。2.利用定义肝细胞癌风险的基因标记，开发一种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成绩单计数技术(nCounter test，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.开发用于评估肝硬变和肝细胞癌预后的生物标志物网络资源。我们新的和现有的代表全球肝硬变患者群体的数据集将被组装成一个公共数据库，使用户的预后分子签名能够快速和轻松地进行临床实用评估。

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.