title: Inactivation of Hippo Pathway Is Significantly Associated with Poor Prognosis in Hepatocellular Carcinoma.
abstract: OBJECTIVE
  The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC.
  
  
  METHODS
  We analyzed gene expression data from Mst1/2(-/-) and Sav1(-/-) mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses.
  
  
  RESULTS
  HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12-2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001).
  
  
  CONCLUSIONS
  Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis.
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bo Hwa
authors.initials: BH
authors.lastname: Sohn
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Internal Medicine, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Jae-Jun
authors.initials: JJ
authors.lastname: Shim
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Department of Pathology, Chonbuk National University Medical School and Hospital, Jeonju, Korea.
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.affiliation: Department of Physiology, Chonbuk National University Medical School and Hospital, Jeonju, Korea.
authors.forename: Soo Mi
authors.initials: SM
authors.lastname: Kim
authors.affiliation: 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, The University of Texas MD Anderson Cancer Center, Houston, Texas. Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jun Eul
authors.initials: JE
authors.lastname: Hwang
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hyun-Sung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Informatics, Center for Genome Science, National Institute of Health, KCDC, Choongchung-Buk-do, Korea.
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Kim
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 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: College of Medicine, Inha University, Incheon, Korea.
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Park
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: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea.
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Dae-Ghon
authors.initials: DG
authors.lastname: Kim
authors.affiliation: Department of Biological Science, Dong-A University, Busan, Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Leem
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kaseb
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Manal M
authors.initials: MM
authors.lastname: Hassan
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Minse
authors.initials: M
authors.lastname: Cha
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, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Korea. jlee@mdanderson.org yypark@amc.seoul.kr.
authors.forename: Yun-Yong
authors.initials: YY
authors.lastname: Park
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea. jlee@mdanderson.org yypark@amc.seoul.kr.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases