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）的加速发病率和沮丧的死亡率（5年生存率<12％）强调了迫切需要改善这种致命的肿瘤的预测和预防。 HCC由于乙型肝炎病毒（HBV），丙型肝炎病毒（HCV），酒精或非酒精性脂肪脂肪肝病（NAFLD）而发展。先前在与HCV相关的肝硬化中鉴定和验证的基质肝硬化肝脏中的186基因预后签名有望确定HCC风险最高的患者，并为HCC预防目标提供线索。对于其他HCC病因，该签名是否也是预后的，仍然未知。此外，该签名尚未被改编为临床上适用的测试。我们的长期目标是为全球肝硬化人群开发临床适用的预后生物标志物，这是由于多种病因引起的，以使更有效，个性化的HCC监视和预防。这里的目的是在非HCV病因中建立186基因签名的预后相关性，确定病因特异性的分子预后因素，实施和完善该签名作为临床上适用的测定，并为预后生物标志物评估开发基因组数据库。我们的核心假设是，186基因的签名是普遍的预后，与病因无关，并且也存在互补的，病因特异性的预后指标。我们将通过以下相互关联的特定目的来检验这些假设，并解决未满足的需求：1。在晚期肝病患者的非HCV病因中建立HCC风险和预后不良的基因特征。我们将对基质肝硬化肝组织进行全基因组表达分析（905个肝硬化和1025个受HBV，HCV，酒精或NAFLD影响的HCC病例），并确认HCC发展的预测能力以及cirrhosis的进展和死亡。病因特异性的预后基因特征也将使用全基因组数据集识别。 2。使用定义HCC风险的基因特征来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成绩单计数技术中实施签名（NCounter分析，纳米串），并优化实验和分析方法。基于转录组测序的预测也将作为临床测试的未来平台进行评估。 3。为肝硬化和HCC的计算机预后生物标志物评估开发网络资源。我们代表全球肝硬化患者群体的新的和现有的数据集将作为一个公共数据库组装，可以快速简便地评估用户的预后分子签名。