title: Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation.
abstract: BACKGROUND
  Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications.
  
  
  RESULTS
  Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3-3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1-2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus-positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus.
  
  
  CONCLUSIONS
  Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification. Please see later in the article for the Editors' Summary.
authors.affiliation: Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Bo Hwa
authors.initials: BH
authors.lastname: Sohn
authors.affiliation: Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Hyun-Sung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Department of Pathology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Yoo
authors.affiliation: ASAN Institute for Life Sciences, Asan Medical Center, Department of Medicine, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Yun-Yong
authors.initials: YY
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Division of Life and Pharmaceutical Sciences, Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, Korea.
authors.forename: Woojin
authors.initials: W
authors.lastname: Jeong
authors.affiliation: Department of Hematology-Oncology, Inje University Haeundae Paik Hospital, Busan, Korea.
authors.forename: Sung Sook
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Park
authors.affiliation: Department of GI Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kaseb
authors.affiliation: Department of Pathology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
authors.forename: Baek Hui
authors.initials: BH
authors.lastname: Kim
authors.affiliation: Department of Surgery, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
authors.forename: Wan Bae
authors.initials: WB
authors.lastname: Kim
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Yeon
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
authors.forename: Kwan Soo
authors.initials: KS
authors.lastname: Byun
authors.affiliation: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Chu
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
authors.affiliation: Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore.
authors.forename: John M
authors.initials: JM
authors.lastname: Luk
authors.affiliation: Department of Surgery, Keimyung University School of Medicine, Daegu, Korea.
authors.forename: Koo Jeong
authors.initials: KJ
authors.lastname: Kang
authors.affiliation: Departments of Molecular Biology and Immunology, Kosin University College of Medicine, Busan, Korea.
authors.forename: Jeonghoon
authors.initials: J
authors.lastname: Heo
authors.affiliation: Department of Pathology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
authors.affiliation: Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D012307:Risk Factors; D050796:STAT3 Transcription Factor / Q000235:genetics; D055815:Young Adult
chemical_list: D050796:STAT3 Transcription Factor