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Original article
A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration
  1. Lindsay Y King1,
  2. Claudia Canasto-Chibuque2,
  3. Kara B Johnson1,
  4. Shun Yip2,
  5. Xintong Chen2,
  6. Kensuke Kojima2,
  7. Manjeet Deshmukh2,
  8. Anu Venkatesh2,
  9. Poh Seng Tan2,3,
  10. Xiaochen Sun2,
  11. Augusto Villanueva4,
  12. Angelo Sangiovanni5,
  13. Venugopalan Nair6,
  14. Milind Mahajan7,
  15. Masahiro Kobayashi8,
  16. Hiromitsu Kumada8,
  17. Massimo Iavarone5,
  18. Massimo Colombo5,
  19. Maria Isabel Fiel9,
  20. Scott L Friedman2,
  21. Josep M Llovet2,10,11,
  22. Raymond T Chung1,
  23. Yujin Hoshida2
  1. 1Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  2. 2Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
  3. 3Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Health System, Singapore
  4. 4Institute of Liver Sciences, King's College London, London, UK
  5. 5M. & A. Migliavacca Center for Liver Disease and 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
  6. 6Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA
  7. 7Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA
  8. 8Department of Hepatology, Toranomon Hospital, Tokyo, Japan
  9. 9Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, USA
  10. 10HCC 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
  11. 11Institució Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Catalonia, Spain
  1. Correspondence to Dr Yujin Hoshida, Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, 1470 Madison Ave, Box 1123, New York, NY 10029, USA; yujin.hoshida{at}mssm.edu Dr Raymond T. Chung, Liver Center and Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Warren 1007, Boston, MA 02114, USA; rtchung{at}partners.org

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.

Design 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/mm3), 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.

  • HEPATITIS C
  • CIRRHOSIS
  • GENE EXPRESSION

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