Experimental and Molecular Medicine

Korean Society for Biochemistry and Molecular Biongy (생화학분자생물학회)
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Clinical significance of APOB inactivation in hepatocellular carcinoma

  • Lee, Gena (Department of Systems Biology, The University of Texas MD Anderson Cancer Center) ;
  • Jeong, Yun Seong (Department of Systems Biology, The University of Texas MD Anderson Cancer Center) ;
  • Kim, Do Won (Department of Systems Biology, The University of Texas MD Anderson Cancer Center) ;
  • Kwak, Min Jun (Department of Systems Biology, The University of Texas MD Anderson Cancer Center) ;
  • Koh, Jiwon (Department of Pathology, Seoul National University College of Medicine) ;
  • Joo, Eun Wook (Department of Gynecology, School of Medicine, Kyung Hee University) ;
  • Lee, Ju-Seog (Department of Systems Biology, The University of Texas MD Anderson Cancer Center) ;
  • Kah, Susie (Department of Internal Medicine, School of Medicine, Kyung Hee University) ;
  • Sim, Yeong-Eun (Department of Internal Medicine, School of Medicine, Kyung Hee University) ;
  • Yim, Sun Young (Department of Systems Biology, The University of Texas MD Anderson Cancer Center)
  • Received : 2018.02.10
  • Accepted : 2018.07.18
  • Published : 2018.11.30
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Abstract

Recent findings from The Cancer Genome Atlas project have provided a comprehensive map of genomic alterations that occur in hepatocellular carcinoma (HCC), including unexpected mutations in apolipoprotein B (APOB). We aimed to determine the clinical significance of this non-oncogenetic mutation in HCC. An Apob gene signature was derived from genes that differed between control mice and mice treated with siRNA specific for Apob (1.5-fold difference; P < 0.005). Human gene expression data were collected from four independent HCC cohorts (n = 941). A prediction model was constructed using Bayesian compound covariate prediction, and the robustness of the APOB gene signature was validated in HCC cohorts. The correlation of the APOB signature with previously validated gene signatures was performed, and network analysis was conducted using ingenuity pathway analysis. APOB inactivation was associated with poor prognosis when the APOB gene signature was applied in all human HCC cohorts. Poor prognosis with APOB inactivation was consistently observed through cross-validation with previously reported gene signatures (NCIP A, HS, high-recurrence SNUR, and high RS subtypes). Knowledge-based gene network analysis using genes that differed between low-APOB and high-APOB groups in all four cohorts revealed that low-APOB activity was associated with upregulation of oncogenic and metastatic regulators, such as HGF, MTIF, ERBB2, FOXM1, and CD44, and inhibition of tumor suppressors, such as TP53 and PTEN. In conclusion, APOB inactivation is associated with poor outcome in patients with HCC, and APOB may play a role in regulating multiple genes involved in HCC development.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF), Korea University Anam Hospital

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