title: A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration.
abstract: OBJECTIVE
  The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression.
  
  
  METHODS
  We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100,000/mm(3)), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years).
  
  
  RESULTS
  In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001).
  
  
  CONCLUSIONS
  A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions.
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lindsay Y
authors.initials: LY
authors.lastname: King
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Canasto-Chibuque
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kara B
authors.initials: KB
authors.lastname: Johnson
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Shun
authors.initials: S
authors.lastname: Yip
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Xintong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Manjeet
authors.initials: M
authors.lastname: Deshmukh
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Venkatesh
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Health System, Singapore.
authors.forename: Poh Seng
authors.initials: PS
authors.lastname: Tan
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Sun
authors.affiliation: Institute of Liver Sciences, King's College London, London, UK.
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, Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sangiovanni
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Venugopalan
authors.initials: V
authors.lastname: Nair
authors.affiliation: Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Milind
authors.initials: M
authors.lastname: Mahajan
authors.affiliation: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
authors.affiliation: M. & A. Migliavacca Center for Liver Disease and 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, 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, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Fiel
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA HCC Translational Research Laboratory, Barcelona Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer Centro de Investigaciones en Red de Enfermedades Hepáticas y Digestivas, Hosptial Clínic Barcelona, Barcelona, Catalonia, Spain Institució Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Catalonia, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
mesh_terms: D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000175:diagnosis / Q000821:virology; D006801:Humans; D015994:Incidence; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012367:RNA, Viral / Q000235:genetics*; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D012367:RNA, Viral
keywords: CIRRHOSIS; GENE EXPRESSION; HEPATITIS C