Molecular Prognostic Indicators in Liver Cirrhosis and Cancer

肝硬化和癌症的分子预后指标

• 批准号: 8698413
• 负责人: Yujin Hoshida
• 金额: $ 69.69万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698413
• 关键词: Address; Affect; Alcohol consumption; Alcohols; Algorithms; Amendment; Bioinformatics; Biological Assay; Body mass index; Cessation of life; Chemoprevention; Cirrhosis; Clinical; Computer Simulation; Data; Data Set; Databases; Deposition; Detection; Development; Diagnostic; Disease; Epidermal Growth Factor Receptor; Etiology; Fibrosis; Future; Gene Expression; Gene Expression Profile; Genes; Genome; Genomics; Glucose; Goals; HBV Cirrhosis; HCV Cirrhosis; Hepatic Stellate Cell; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Incidence; Internet; Laboratories; Liver; Liver Cirrhosis; Liver diseases; Malignant neoplasm of liver; Meta-Analysis; Methods; Modeling; Molecular; Molecular Profiling; Multivariate Analysis; Neoplasms; Outcome; Patients; Population; Prevention; Primary carcinoma of the liver cells; Prognostic Factor; Prognostic Marker; Rattus; Research; Resources; Risk; Signal Transduction; Subgroup; Technology; Testing; Tissues; Transcript; analytical method; base; cancer prevention; clinical practice; cohort; design; digital; genome-wide; improved; lipid metabolism; mortality; nano-string; non-alcoholic fatty liver; outcome forecast; patient population; prognostic; prospective; public health relevance; research clinical testing; transcriptome sequencing; viral DNA

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.

描述（由申请人提供）：肝细胞癌 (HCC) 的发病率和死亡率不断上升（5 年生存率 <12%），凸显了改善这种致命肿瘤的预测和预防的迫切需要。 HCC 是由乙型肝炎病毒 (HBV)、丙型肝炎病毒 (HCV)、酒精或非酒精性脂肪肝病 (NAFLD) 导致的晚期纤维化发展而来。间质性肝硬化中的 186 个基因预后特征先前在 HCV 相关肝硬化中被识别和验证，有望识别 HCC 风险最高的患者，并为 HCC 预防目标提供线索。目前尚不清楚该特征是否也可用于其他 HCC 病因的预后。此外，该特征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引起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。这里的目标是建立非 HCV 病因中 186 个基因特征的预后相关性，识别病因特异性分子预后因素，实施和完善该特征作为临床适用的检测，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，无论病因如何，186 个基因特征都具有普遍的预后作用，并且还存在互补的、针对病因的预后指标。我们将测试这些假设，并通过以下相互关联的具体目标解决未满足的需求： 1. 在患有非 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 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来识别病因学特异性的预后基因特征。 2. 使用定义 HCC 风险的基因特征开发临床适用的预后测试。我们将在专为临床实验室设计的数字转录本计数技术（nCounter Assay、NanoString）中实施签名，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未来潜在的临床测试平台。 3. 开发用于肝硬化和 HCC 计算机预后生物标志物评估的网络资源。我们代表全球肝硬化患者群体的新数据集和现有数据集将被组装成一个公共数据库，以便能够快速、轻松地对用户的预后分子特征进行临床实用性评估。