title: A Global Risk Score (GRS) to Simultaneously Predict Early and Late Tumor Recurrence Risk after Resection of Hepatocellular Carcinoma.
abstract: OBJECTIVE
  Recurrence of hepatocellular carcinoma can arise from the primary tumor ("early recurrence") or de novo from tumor formation in a cirrhotic environment ("late recurrence"). We aimed to develop one simple gene expression score applicable in both the tumor and the surrounding liver that can predict the recurrence risk.
  
  
  METHODS
  We determined differentially expressed genes in a cell model of cancer aggressiveness. These genes were first validated in three large published data sets of hepatocellular carcinoma from which we developed a seven-gene risk score.
  
  
  RESULTS
  The gene score was applied on two independent large patient cohorts. In the first cohort, with only tumor data available, it could predict the recurrence risk at 3 years after resection (68 ± 10% vs 35 ± 7%, P = .03). In the second cohort, when applied on the tumor, this gene score predicted early recurrence (62 ± 5% vs 37 ± 4%, P < .001), and when applied on the surrounding liver tissue, the same genes also correlated with late recurrence. Four patient classes with each different time patterns and rates of recurrence could be identified based on combining tumor and liver scores. In a multivariate Cox regression analysis, our gene score remained significantly associated with recurrence, independent from other important cofactors such as disease stage (P = .007).
  
  
  CONCLUSIONS
  We developed a Global Risk Score that is able to simultaneously predict the risk of early recurrence when applied on the tumor itself, as well as the risk of late recurrence when applied on the surrounding liver tissue.
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University Hospitals Leuven & KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Dekervel
authors.affiliation: Department of Electrical Engineering (ESAT), STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics/iMinds Medical IT, KU Leuven, Kasteelpark Arenberg 10, 3000, Leuven, Belgium.
authors.forename: Dusan
authors.initials: D
authors.lastname: Popovic
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University Hospitals Leuven & KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Hannah
authors.initials: H
authors.lastname: van Malenstein
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University Hospitals Leuven & KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Windmolders
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven & Department of Microbiology and Immunology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Line
authors.initials: L
authors.lastname: Heylen
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University Hospitals Leuven & KU Leuven, Herestraat 49, 3000, Leuven, Belgium; Department of Pathology, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University Hospitals Leuven & KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Ashenafi
authors.initials: A
authors.lastname: Bulle
authors.affiliation: Department of Electrical Engineering (ESAT), STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics/iMinds Medical IT, KU Leuven, Kasteelpark Arenberg 10, 3000, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: De Moor
authors.affiliation: Department of Clinical Digestive Oncology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University Hospitals Leuven & KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University Hospitals Leuven & KU Leuven, Herestraat 49, 3000, Leuven, Belgium; Department of Clinical Digestive Oncology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Verslype
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University Hospitals Leuven & KU Leuven, Herestraat 49, 3000, Leuven, Belgium. Electronic address: jos.vanpelt@med.kuleuven.be.
authors.forename: Jos
authors.initials: J
authors.lastname: van Pelt