title: Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma.
abstract: OBJECTIVE
  In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. Although gene expression signatures have been associated with outcome, there is no method to predict recurrence based on combined clinical, pathology, and genomic data (from tumor and cirrhotic tissue). We evaluated gene expression signatures associated with outcome in a large cohort of patients with early stage (Barcelona-Clinic Liver Cancer 0/A), single-nodule HCC and heterogeneity of signatures within tumor tissues.
  
  
  METHODS
  We assessed 287 HCC patients undergoing resection and tested genome-wide expression platforms using tumor (n = 287) and adjacent nontumor, cirrhotic tissue (n = 226). We evaluated gene expression signatures with reported prognostic ability generated from tumor or cirrhotic tissue in 18 and 4 reports, respectively. In 15 additional patients, we profiled samples from the center and periphery of the tumor, to determine stability of signatures. Data analysis included Cox modeling and random survival forests to identify independent predictors of tumor recurrence.
  
  
  RESULTS
  Gene expression signatures that were associated with aggressive HCC were clustered, as well as those associated with tumors of progenitor cell origin and those from nontumor, adjacent, cirrhotic tissues. On multivariate analysis, the tumor-associated signature G3-proliferation (hazard ratio [HR], 1.75; P = .003) and an adjacent poor-survival signature (HR, 1.74; P = .004) were independent predictors of HCC recurrence, along with satellites (HR, 1.66; P = .04). Samples from different sites in the same tumor nodule were reproducibly classified.
  
  
  CONCLUSIONS
  We developed a composite prognostic model for HCC recurrence, based on gene expression patterns in tumor and adjacent tissues. These signatures predict early and overall recurrence in patients with HCC, and complement findings from clinical and pathology analyses.
authors.affiliation: HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Liver Unit, Hospital Clinic, Barcelona, Spain.
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.forename: Carlo
authors.initials: C
authors.lastname: Battiston
authors.forename: Victoria
authors.initials: V
authors.lastname: Tovar
authors.forename: Daniela
authors.initials: D
authors.lastname: Sia
authors.forename: Clara
authors.initials: C
authors.lastname: Alsinet
authors.forename: Helena
authors.initials: H
authors.lastname: Cornella
authors.forename: Arthur
authors.initials: A
authors.lastname: Liberzon
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
authors.forename: Swan N
authors.initials: SN
authors.lastname: Thung
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruix
authors.forename: Philippa
authors.initials: P
authors.lastname: Newell
authors.forename: Craig
authors.initials: C
authors.lastname: April
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.forename: Sasan
authors.initials: S
authors.lastname: Roayaie
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.forename: Myron E
authors.initials: ME
authors.lastname: Schwartz
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006498:Hepatectomy; D006801:Humans; D015994:Incidence; D007558:Italy / Q000453:epidemiology; D007564:Japan / Q000453:epidemiology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000453:epidemiology; D011379:Prognosis; D013030:Spain / Q000453:epidemiology; D015996:Survival Rate; D014481:United States / Q000453:epidemiology
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm