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Cancer Cell. 2016 Dec 12;30(6):879-890. doi: 10.1016/j.ccell.2016.11.004.

Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition.

Author information

1
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
2
Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
3
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Gastroenterology and Hepatology, Geneva University Hospital, 41205 Geneva, Switzerland.
6
PharmAkea Therapeutics, San Diego, CA 92109, USA.
7
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
8
Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9
Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, and Faculty of Medicine, College of Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
10
Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, and Faculty of Medicine, College of Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
11
Department of Hepatology, Toranomon Hospital, Tokyo 105-0001, Japan.
12
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
13
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
14
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
15
Division of Thoracic Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
16
M. & A. Migliavacca Center for Liver Disease and 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.
17
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Liver Cancer Translational Research Laboratory, Barcelona Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Institució Catalana de Recerca i Estudis Avançats, Catalonia, 08036 Barcelona, Spain.
18
Cancer Program, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
19
Pulmonary and Critical Care Unit, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
20
Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67081 Strasbourg, France; Institut Hospitalo-Universitaire, Pôle hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France; Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
21
Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
22
Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bfuchs@mgh.harvard.edu.
23
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: yujin.hoshida@mssm.edu.

Abstract

Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention.

KEYWORDS:

cancer chemoprevention; gene signature; hepatocellular carcinoma; prognostic prediction; transcriptome

PMID:
27960085
PMCID:
PMC5161110
DOI:
10.1016/j.ccell.2016.11.004
[Indexed for MEDLINE]
Free PMC Article

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