Liver – Fred Hutchinson Cancer Research Center (Coordinating Center)

Brief Description of Project:

"Hepatitis C Virus-associated Hepatocellular Carcinoma" is an international, multi-institutional research project to identify biomarkers that reveal the progression of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection. We will determine which of these biomarkers may be effective markers for early diagnosis, which may be effective markers for disease recurrence after ablation or resection, and which may predict risk of progression. Samples from several tissue banks (including matching tissue and serum samples) will be available and the samples will be processed in the proteomics laboratories at FHCRC and NTU.

The World Health Organization (WHO) estimates that about 170 million people are chronically infected with HCV worldwide. These patients are at high risk of developing liver cirrhosis and HCC. The pathway that leads from HCV to HCC is well defined, beginning with chronic inflammation of the liver and proceeding through fibrosis and cirrhosis to HCC. In chronically infected HCV patients, the progression from chronic inflammation to the onset of cirrhosis often takes 20 to 40 years. Once cirrhosis has developed, between 3% and 8% of HCV patients will progress to HCC annually.

Currently, the diagnostic marker for HCC is alpha-fetoprotein (AFP). However, the sensitivity of AFP runs as low .65 and the specificity of AFP runs as low as .69. We hope to identify some candidate markers with a significantly higher sensitivity and a significantly higher specificity.

The research project will have two specific goals:

• - identification of serum markers for early detection of HCC in cirrhotic patients, and
• - identification of serum markers associated with the states of fibrosis progression

Three basic strategies will be used in this project: tissue-based, serum-based, and animal model-based. In the tissue-based strategy, we will compare the proteomic profiles of neoplastic liver tissue with adjacent tissue. In the serum-based strategy, we will compare samples from healthy individuals, samples from patients with fibrosis at different stages, and samples from patients with HCC. In the animal model-based strategy, xenografts will be developed by injecting HCC cell lines into nude mice. Animal models of HCV-related HCC are currently in development.

Team Members and Expertise:

Laura BERETTA, Ph.D. (Fred Hutchinson Cancer Research Center – Biomarker Team PI) [lberetta@fhcrc.org]
Dr. Beretta is an Associate Member at Fred Hutchinson Cancer Research Center and she also holds an appointment as an Associate Professor in the Department of Pathology at the University of Washington. Her current research focuses on the hepatitis C virus (HCV) and associated liver cancer. Dr. Beretta uses a combination of proteomics and gene silencing technologies to identify cellular proteins involved in HCV replication in hepatocytes. Her group has also embarked on a major effort to integrate genomics, transcriptomics and proteomics for identifying new markers for early HCC diagnosis and for identifying defective signaling pathways and their signatures in hepatocytic transformation. Dr. Beretta is a founding member of the Board of Directors of U.S. HUPO (Human Proteome Organisation) and she currently serves as chair of the HUPO Human Liver Proteome Project (HLPP). Dr. Beretta is PI of grants from NIDDK and NIAID and also receives support from the Early Detection Research Network (EDRN) at NCI for her study on HCC biomarkers.

Christian BRÉCHOT, Ph.D. (Institut National de la Santé et de la Recherche Médicale) [brechot@tolbiac.inserm.fr]
Dr. Bréchot is the Director General of INSERM, the French National Institute of Health and medical Research. He is a specialist in hepatitis B virus (HBV) and hepatitis C virus (HCV) and the progression from chronic hepatitis infection to liver cancer. In addition he serves as head of the French National Reference Center for the Epidemiology of Viral Hepatitis and his clinical practice is based at the Necker and Sick Childrens Hospital. Dr. Bréchot's work focuses on the development of new therapies for the treatment of hepatitis and on the mechanisms by which HBV and HCV infections develop into HCC, including an emphasis on viral replication strategies and the impact genetic risk factors that enhance or retard disease progression. He also serves as President of the French National Genome Research Consortium and as a member of the Executive Council of the Human Proteome Organisation (HUPO) and as Co-chair of the Human Liver Proteome Project (HLPP).

Chi-Ling CHEN, Ph.D. (National Taiwan University) [chlnchen@ntumc.org]
Dr. Chen is a Research Assistant Professor in the Graduate Institute of Clinical Medicine at the National Taiwan University College of Medicine (NTUCM). She is an epidemiologist and her role in the consortium will include identification and characterization of the clinical samples (tissue and serum) and assembling the related clinical description from the patient records. She will also coordinate shipment of the specimens from Taiwan to Fred Hutchinson Cancer Research Center (FHCRC) in Seattle.

Chien-Hung CHEN, M.D., Ph.D. (National Taiwan University) [chenhcc@ntumc.org]
Dr. Chen is a Clinical Assistant Professor in the Department of Internal Medicine at the National Taiwan University College of Medicine (NTUCM). He has spent two years at the Johns Hopkins Medical Center, Baltimore, Maryland, studying DNA vaccines. His recent research interests also include the search for biomarkers for HCC using proteomic approaches.

Ding-Shinn CHEN, M.D. (National Taiwan University) [dschen@ntumc.org]
Dr. Chen is Dean and Professor of Medicine, National Taiwan University College of Medicine (NTUCM). His research interest is in the basic and clinical aspects of viral hepatitis and liver disease, especially cirrhosis and hepatocellular carcinoma (HCC). He has lead his research team at NTUCM for more than two decades and his team has contributed much to the natural history, treatment and prevention of hepatitis B infection and hepatitis C infection. Based on his achievements he was elected as a member of Academia Sinica (the national academy in Taiwan) in 1992, and was elected as a foreign associate of the U.S. National Academy of Sciences in 2005. He will serve as the coordinator for this project at National Taiwan University.

Pei-Jer CHEN, M.D., Ph.D. (National Taiwan University)
Dr. Chen is a Professor and the current Director of the Graduate Institute of Clinical Medicine at the National Taiwan University College of Medicine (NTUCM). After he graduated from NTUCM, he received his Ph.D. from the University of Pennsylvania. Trained as a molecular virologist/biologist, he is the key person in molecular studies on the NTUCM team. He has contributed significantly to our knowledge of the molecular virology of the hepatitis B virus, the hepatitis C virus, and the hepatitis D virus. In recent years, he has also focused his research on the genomic aspects of HCC.

Jia-Horng KAO, M.D., Ph.D. (National Taiwan University) [kjh@ntumc.org]
Dr. Kao is the Director of the Hepatitis Research Center at the National Taiwan University Hospital and a Professor in the Graduate Institute of Clinical Medicine at the National Taiwan University College of Medicine (NTUCM). His research focuses on the hepatitis viruses and chronic liver diseases, including hepatocellular carcinoma (HCC). He will contribute to the team in collection of the clinical samples (tissue and serum) for identification of the molecular markers of clinical pathology, disease progression, tumor recurrence and prognosis, as well as the putative tumor suppressor gene(s) associated with HCC.

Ming-Yang LAI, M.D., Ph.D. (National Taiwan University) [mylai@ntumc.org]
Dr. Lai is a Professor and the immediate past Director of the Graduate Institute of Clinical Medicine at the National Taiwan University College of Medicine (NTUCM). He has worked on the treatment of chronic hepatitis C infection for more than 15 years and is the key person in the NTUCM team in pioneering combination therapy with interferon alpha and ribavirin. His recent research interest includes a proteomics approach to the diagnosis of liver fibrosis.

Shwu-Bin LIN, Ph.D. (National Taiwan University) [sblin@ntumc.org]
Dr. Chen is a Professor in the Department of Clinical Laboratory Sciences and Medical Biotechnology at the National Taiwan University College of Medicine (NTUCM). She received her Ph.D from the Johns Hopkins University. She is a biochemist and molecular biologist specializing in the structure and function of nucleic acids and proteins. She has focused on biochemistry and molecular signaling in liver disease, especially in hepatocellular carcinoma, for more than ten years. Her recent research has focused on proteomic approaches for biomarker discovery for liver fibrosis and cirrhosis.

Chun-Jen LIU, M.D., Ph.D. (National Taiwan University) [cjliu@ntumc.org]
Dr. Liu is on the staff of the Department of Internal Medicine at the National Taiwan University Hospital and he also holds an appointment as a Clinical Assistant Professor in the Department of Internal Medicine at the National Taiwan University College of Medicine (NTUCM). His work focuses on the pathogenesis and treatment of chronic viral hepatitis and he is interested in the woodchuck animal model for chronic viral hepatitis and hepatocarcinogenesis. He is also interested in the role of various hepatitis B virus (HBV) factors, including genome-wide mutants and genotypes in the progression of chronic HBV infection. He will be in charge of the clinical data and sample collection.

Martin MCINTOSH, Ph.D. (Fred Hutchinson Cancer Research Center) [mmintos@fhcrc.org]
Dr. McIntosh is an Associate Member in the Division of Public Health Sciences at the FHCRC and serves as Head of the FHCRC Comparative Proteomics Computational Group. He also holds an appointment as an Associate Professor in the Department of Biostatistics at the University of Washington. He is a founding member of the Board of Directors of U.S. HUPO (Human Proteome Organisation). Dr. McIntosh is PI of the early detection project of the FHCRC's ovarian cancer SPORE and Co-PI of a NCI-funded project for predicting cancer progression in cervical cancer. He is also Co-Investigator on three NCI and DOD-funded research projects for early detection biomarker discovery and evaluation. He has authored several articles on theoretical and practical considerations for combining biomarkers and on algorithms for early detection of cancer.

Ya-Chien YANG, Ph.D. (National Taiwan University) [ycyang@ntumc.org]
Dr. Yang is an Assistant Professor in the Department of Clinical Laboratory Sciences and Medical Biotechnology at the National Taiwan University College of Medicine (NTUCM). Her Ph.D. dissertation was on genetic analysis of human retroviruses. She specializes in immunology and serology and is experienced in molecular genetic testing for colorectal cancer. She will participate in proteomic analysis to identify molecular markers for clinical pathology, chronological progression, tumor recurrence, and prognosis (as well as the putative tumor suppressor gene(s) associated with hepatocellular carcinoma (HCC).