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A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection
  1. David Y Zhang1,
  2. Nicolas Goossens2,3,
  3. Jinsheng Guo1,4,
  4. Ming-Chao Tsai1,5,
  5. Hsin-I Chou1,
  6. Civan Altunkaynak1,
  7. Angelo Sangiovanni6,
  8. Massimo Iavarone6,
  9. Massomo Colombo6,
  10. Masahiro Kobayashi7,
  11. Hiromitsu Kumada7,
  12. Augusto Villanueva1,2,
  13. Josep M Llovet1,2,8,9,
  14. Yujin Hoshida1,2,
  15. Scott L Friedman1,2
  1. 1Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  2. 2Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  3. 3Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
  4. 4Division of Digestive Diseases, Zhongshang Hospital and Fudan University, Shanghai, China
  5. 5Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
  6. 61st Division of Gastroenterology, M. & A. Migliavacca Center for Liver Disease, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
  7. 7Department of Hepatology, Toranomon Hospital, Tokyo, Japan
  8. 8Liver Cancer Translational Research Lab, Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, Centro de Investigaciones en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain
  9. 9Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
  1. Correspondence to Scott L. Friedman, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Box 1123, New York, NY 10029, USA; scott.friedman{at}


Objective We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells and assessed the prognostic capability of their expression in cirrhosis.

Design We defined a hepatic stellate cell gene signature by comparing stellate, immune and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables, using overall survival as the primary clinical outcome. This signature was derived in a retrospective–prospective cohort of hepatitis C-related early-stage cirrhosis (prognostic index derivation set) and validated in an independent retrospective cohort of patients with postresection hepatocellular carcinoma (HCC) (n=82, prognostic index validation set). We then examined the association between hepatic stellate cell signature expression and decompensation, HCC incidence and progression of Child–Pugh class as additional outcomes in the prognostic index derivation set, and HCC recurrence as an additional outcome in the validation set. We tested whether hepatic stellate cell signature expression is predictive of death, decompensation, progression of Child–Pugh class and HCC incidence in a retrospective–prospective cohort of patients with hepatitis C cirrhosis. In the prognostic index derivation cohort (n=216), 66 (31%) died, 71 (34%) developed hepatic decompensation, 66 (31%) experienced progression of Child–Pugh class and 65 (30%) developed HCC. In the prognostic index validation cohort (n=82), 32 (39%) died and 65 (79%) developed tumour recurrence.

Results The 122-gene hepatic stellate cell signature consists of genes encoding extracellular matrix proteins and developmental factors and correlates with the extent of fibrosis in human, mouse and rat datasets. The hepatic stellate cell signature contains several cell surface genes previously established as stellate cell-specific, as well as PCDH7, a novel protocadherin stellate cell surface marker. Importantly, association of clinical prognostic variables with overall survival (c-index: 0.66, 95% CI 0.59 to 0.74) was improved by adding the hepatic stellate cell signature (c-index: 0.70, 95% CI 0.62 to 0.78); we used these results to define a prognostic index in the derivation set. In the validation set, the same prognostic index was associated with overall survival (c-index: 0.62, 95% CI 0.51 to 0.72). For other clinical outcomes examined, the prognostic index was associated with decompensation (c-index: 0.62, 95% CI 0.55 to 0.69), HCC (c-index: 0.63, 95% CI 0.56 to 0.71) and progression of Child–Pugh class (c-index: 0.70, 95% CI 0.63 to 0.78) in the derivation set, and HCC recurrence (c-index: 0.54, 95% CI 0.46 to 0.62) in the validation set.

Conclusions This work highlights the unique transcriptional niche of stellate cells, and identifies potential stellate cell targets for tracking, targeting and isolation. Hepatic stellate cell signature expression may identify patients with HCV cirrhosis or postresection HCC with poor prognosis.


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