title: Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition.
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.
authors.affiliation: 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.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Won Min
authors.initials: WM
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sarani
authors.initials: S
authors.lastname: Ghoshal
authors.affiliation: 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.
authors.forename: Rosa S
authors.initials: RS
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: C Billie
authors.initials: CB
authors.lastname: Bian
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: 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.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Anu
authors.initials: A
authors.lastname: Venkatesh
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goossens
authors.affiliation: PharmAkea Therapeutics, San Diego, CA 92109, USA.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Bain
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.affiliation: 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.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Koh
authors.affiliation: 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.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Abtah
authors.affiliation: 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.
authors.forename: Noor B
authors.initials: NB
authors.lastname: Ahmad
authors.affiliation: 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.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hoshida
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Erstad
authors.affiliation: Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Gunasekaran
authors.affiliation: 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.
authors.forename: Youngmin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Ming-Lung
authors.initials: ML
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Wan-Long
authors.initials: WL
authors.lastname: Chuang
authors.affiliation: 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.
authors.forename: Chia-Yen
authors.initials: CY
authors.lastname: Dai
authors.affiliation: Department of Hepatology, Toranomon Hospital, Tokyo 105-0001, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Hepatology, Toranomon Hospital, Tokyo 105-0001, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Beppu
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Milind
authors.initials: M
authors.lastname: Mahajan
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Venugopalan D
authors.initials: VD
authors.lastname: Nair
authors.affiliation: Division of Thoracic Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lanuti
authors.affiliation: 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.
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: 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.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sangiovanni
authors.affiliation: 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.
authors.forename: Massimo
authors.initials: M
authors.lastname: Iavarone
authors.affiliation: 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.
authors.forename: Massimo
authors.initials: M
authors.lastname: Colombo
authors.affiliation: 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.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Aravind
authors.initials: A
authors.lastname: Subramanian
authors.affiliation: Pulmonary and Critical Care Unit, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
authors.affiliation: 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.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.affiliation: 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.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.affiliation: Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Myron E
authors.initials: ME
authors.lastname: Schwarz
authors.affiliation: Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bfuchs@mgh.harvard.edu.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Fuchs
authors.affiliation: 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.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000517:prevention & control*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000517:prevention & control*; D008246:Lysophospholipids / Q000096:biosynthesis*; D051381:Rats; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008246:Lysophospholipids; C032881:lysophosphatidic acid
keywords: cancer chemoprevention; gene signature; hepatocellular carcinoma; prognostic prediction; transcriptome