Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma

Authors

  • Elisa Wurmbach,

    Corresponding author
    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
    • Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, Madison Avenue 1468, Box, 1178, New York, NY 10029
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  • Ying-bei Chen,

    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
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  • Greg Khitrov,

    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
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  • Weijia Zhang,

    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
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  • Sasan Roayaie,

    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
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  • Myron Schwartz,

    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
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  • Isabel Fiel,

    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
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  • Swan Thung,

    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
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  • Vincenzo Mazzaferro,

    1. National Cancer Institute, Milan, Italy
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  • Jordi Bruix,

    1. BCLC Group, IDIBAPS, Liver Unit, Hospital Clinic, Barcelona, Spain
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  • Erwin Bottinger,

    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
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  • Scott Friedman,

    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
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  • Samuel Waxman,

    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
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  • Josep M. Llovet

    Corresponding author
    1. Mount Sinai Liver Cancer Program (Division of Liver Disease, Division of Hematology/Oncology, Department of Medicine; Recanati-Miller Transplantation Institute; Department of Pathology), Mount Sinai School of Medicine, New York, NY
    2. BCLC Group, IDIBAPS, Liver Unit, Hospital Clinic, Barcelona, Spain
    • Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Madison Avenue 1425, 11F-70, Box 1104, New York, NY 10029
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    • Josep M. Llovet is Professor of Research at Institut Català de Recerca Avancada (ICREA, IDIBAPS, Hospital Clínic).

    • fax: 212-241-2138/212-996-9688


  • Potential conflict of interest: Nothing to report.

Abstract

Although HCC is the third-leading cause of cancer-related deaths worldwide, there is only an elemental understanding of its molecular pathogenesis. In western countries, HCV infection is the main etiology underlying this cancer's accelerating incidence. To characterize the molecular events of the hepatocarcinogenic process, and to identify new biomarkers for early HCC, the gene expression profiles of 75 tissue samples were analyzed representing the stepwise carcinogenic process from preneoplastic lesions (cirrhosis and dysplasia) to HCC, including 4 neoplastic stages (very early HCC to metastatic tumors) from patients with HCV infection. We identified gene signatures that accurately reflect the pathological progression of disease at each stage. Eight genes distinguish between control and cirrhosis, 24 between cirrhosis and dysplasia, 93 between dysplasia and early HCC, and 9 between early and advanced HCC. Using quantitative real-time reverse-transcription PCR, we validated several novel molecular tissue markers for early HCC diagnosis, specifically induction of abnormal spindle-like, microcephaly-associated protein, hyaluronan-mediated motility receptor, primase 1, erythropoietin, and neuregulin 1. In addition, pathway analysis revealed dysregulation of the Notch and Toll-like receptor pathways in cirrhosis, followed by deregulation of several components of the Jak/STAT pathway in early carcinogenesis, then upregulation of genes involved in DNA replication and repair and cell cycle in late cancerous stages. Conclusion: These findings provide a comprehensive molecular portrait of genomic changes in progressive HCV-related HCC. (HEPATOLOGY 2007;45:938–947.)

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