Integrative genomic analysis in hepatocellular carcinoma

肝细胞癌的综合基因组分析

• 批准号: 8123103
• 负责人: JOSEP M LLOVET
• 金额: $ 24.29万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-10 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123103
• 关键词: Advanced Malignant Neoplasm; Biological Markers; Cancer Etiology; Candidate Disease Gene; Cessation of life; Characteristics; Chemopreventive Agent; Chromosome Mapping; Classification; Clinical; Clinical Data; Clinics and Hospitals; Collaborations; DNA Microarray Chip; Data; Detection; Diagnosis; Diagnostic; Diffuse; Disease; Disease Progression; Disseminated Malignant Neoplasm; Early Detection Research Network; Early Diagnosis; Ensure; Etiology; European; Excision; Gene Expression; Gene Expression Profile; Genes; Genome; Genomics; Glioma; Health; Hepatitis C virus; Hepatocarcinogenesis; Histology; Human Genome; Incidence; Informatics; Institutes; Knowledge; Lesion; Liver; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Methods; Microarray Analysis; Molecular; Molecular Abnormality; Molecular Genetics; Molecular Profiling; Mutation; National Cancer Institute; Neoplasms; New York; Nodule; Normal tissue morphology; Oncogenes; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Population; Prevention; Primary carcinoma of the liver cells; Public Health; Recurrence; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Scheme; Screening procedure; Single Nucleotide Polymorphism; Staging; Surveillance Program; Testing; Therapeutic; Time; Tissue Banking; Tissue Banks; Tissues; Training; Tumor Suppressor Genes; Tumor Suppressor Proteins; Universities; Validation; Western Europe; base; cancer recurrence; clinical practice; cohort; density; effective therapy; genome-wide; glypican 3; melanoma; novel; novel diagnostics; novel marker; outcome forecast; prognostic; programs; prospective; response; survivin; tumor

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide with the most rapidly rising cancer incidence in the US and Western Europe. The disease is a major public health problem, for which there are no molecular diagnostics and limited effective treatment options. The hypothesis of the project is that knowledge of the gene expression profiles and the somatic genetic alterations of HCC will enable the identification of tumor suppressor genes or oncogenes involved in the pathogenesis of the disease, and will provide markers of early detection and new treatment targets. The identification of gene signatures predictive of clinical outcomes will enable a molecular classification of HCC. For that purpose we will test 230 samples [including 20 dysplastic nodules and 100 paired HCV- related HCC/non-tumoral cirrhotic liver]. We already have collected 214 samples from patients in 3 referral HCC Units: Mount Sinai, New York; Hospital Clinic Barcelona (Collaborator #2); National Cancer Institute, Milan (Collaborator #3). Specific aims: Aim #1: Characterize the gene expression profiles of dysplastic lesions and hepatocellular carcinoma in HCV infected patients. 1a. Determine the genes and pathways involved in hepatocarcinogenesis, by genome- wide gene expression analysis. By using genome-wide microarray technology profiling of 38,500 genes, (Affymetrix, Genechip Human Genome-U133 Plus 2.0), we have identified molecular signatures that classify dysplastic nodules, early tumors and advanced cancers in a preliminary set of 73 samples. We will expand the analysis to 230 samples. 1b. Identify a molecular signature predictive of HCC recurrence and survival. A gene signature able to discriminate good and poor outcomes will be analyzed in 85 patients undergoing resection for HCC in which complete clinical data has been recorded. Multivariate approaches will ensure a proper integration of the clinical and molecular data. Aim #2: To define the extent of structural alterations in the HCC genome using high-density single nucleotide polymorphisms arrays interrogating 500,000 genomic loci. To integrate emerging genetic maps with paired expression data to identify candidate tumor suppressors and oncogenes. We will apply high-density 500K SNP arrays to the analysis of structural somatic genetic alterations in HCC, in collaboration with the Dr. William Sellers/Matthew Meyerson's group in Dana-Farber Institute, Harvard (Collaborator #1). By using integrative genomic analysis of the molecular profiling and genetic disturbances we'll identify novel tumor suppressors or oncogenes, which may constitute new targets for chemopreventive and therapeutic strategies. Aim #3: Identify molecular biomarkers for the diagnosis of early HCC. #3a: Identification of biomarkers. We have identified by Real-Time RT-PCR a gene signature of 3 genes (Glypican-3, Survivin, LYVE-1) able to discriminate between dysplastic lesions from early cancer with an accuracy of 94%. By microarray technology, we have preliminary data with a set of 93 potential candidate genes for the identification of new biomarkers. #3b: To validate the molecular signature for the diagnosis of early HCC in cirrhotic patients undergoing screening. The gene- signature identified will be validated in the clinical practice in a testing set of 80 samples from nodules between 0.5-2cm obtained from a prospective cohort of HCV-cirrhotic patients (Collaborator #2, University of Barcelona).

描述（由申请人提供）：肝细胞癌（HCC）是全球癌症相关死亡的第三大原因，在美国和西欧的癌症发病率上升最快。该疾病是一个重大的公共卫生问题，对此没有分子诊断方法，有效的治疗方案有限。该项目的假设是，HCC的基因表达谱和体细胞遗传学改变的知识将能够识别参与疾病发病机制的肿瘤抑制基因或癌基因，并将提供早期检测和新的治疗靶点的标志物。识别预测临床结果的基因特征将使HCC的分子分类成为可能。为此，我们将检测230个样本[包括20个发育不良结节和100个配对的HCV相关HCC/非肿瘤性肝硬化]。我们已经从3个转诊HCC单位的患者中收集了214份样本：Mount Sinai，纽约; Hospital Clinic Barcelona（合作者#2）; National Cancer Institute，Milan（合作者#3）。具体目标：目标#1：描述HCV感染患者中异型增生病变和肝细胞癌的基因表达谱。1a.通过全基因组基因表达分析，确定肝癌发生的相关基因和通路.通过使用38，500个基因的全基因组微阵列技术分析（Affyphire，Genechip Human Genome-U133 Plus 2.0），我们在73个样本的初步组中鉴定了对发育不良结节、早期肿瘤和晚期癌症进行分类的分子特征。我们将把分析范围扩大到230个样本。1b.确定预测HCC复发和生存的分子标记。将在85例接受HCC切除术的患者中分析能够区分良好和不良结局的基因签名，其中已记录完整的临床数据。多变量方法将确保临床和分子数据的适当整合。目标二：使用高密度单核苷酸多态性芯片检测500，000个基因组位点，确定HCC基因组结构改变的程度。整合新兴的基因图谱与配对表达数据，以确定候选肿瘤抑制基因和癌基因。我们将与哈佛Dana-Farber研究所的William Sellers/Matthew Meyerson博士（合作者#1）合作，应用高密度500 K SNP阵列分析HCC的结构体细胞遗传学改变。通过使用分子谱和遗传紊乱的整合基因组分析，我们将鉴定新的肿瘤抑制因子或癌基因，这可能构成化学预防和治疗策略的新靶点。目的#3：鉴定用于诊断早期HCC的分子生物标志物。#3a：生物标志物的鉴定。我们已经通过实时RT-PCR鉴定了3个基因（磷脂酰肌醇蛋白聚糖-3、存活素、LYVE-1）的基因特征，其能够以94%的准确度区分发育异常病变与早期癌症。通过微阵列技术，我们获得了93个潜在候选基因的初步数据，用于鉴定新的生物标志物。#3b：验证在接受筛查的前列腺癌患者中诊断早期HCC的分子特征。将在临床实践中在来自0.5-2cm之间的结节的80个样品的测试组中验证所鉴定的基因签名，所述结节从HCV感染患者的前瞻性队列获得（合作者#2，巴塞罗那大学）。

项目成果

Tissue biomarkers as predictors of outcome and selection of transplant candidates with hepatocellular carcinoma.

• DOI: 10.1002/lt.22340
• 发表时间: 2011-10
• 期刊: LIVER TRANSPLANTATION
• 影响因子: 4.6
• 作者: Llovet, Josep M.;Paradis, Valerie;Kudo, Masatoshi;Zucman-Rossi, Jessica
• 通讯作者: Zucman-Rossi, Jessica

Hippo tumor supressor pathway: novel implications for the treatment of hepatocellular carcinoma.

• DOI: 10.1053/j.gastro.2010.06.036
• 发表时间: 2010-08
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Lachenmayer A;Hoshida Y;Llovet JM
• 通讯作者: Llovet JM

New strategies in hepatocellular carcinoma: genomic prognostic markers.

• DOI: 10.1158/1078-0432.ccr-09-1811
• 发表时间: 2010-10-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Villanueva A;Hoshida Y;Toffanin S;Lachenmayer A;Alsinet C;Savic R;Cornella H;Llovet JM
• 通讯作者: Llovet JM

Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies.

• DOI: 10.1038/onc.2012.617
• 发表时间: 2013-10-10
• 期刊: Oncogene
• 影响因子: 8

Testing molecular therapies in hepatocellular carcinoma: the need for randomized phase II trials.

测试肝细胞癌的分子疗法：随机 II 期试验的需要。

• DOI: 10.1200/jco.2008.19.1973
• 发表时间: 2009
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: Llovet,JosepM;Bruix,Jordi
• 通讯作者: Bruix,Jordi