TY - JOUR
T1 - Clinical significance of APOB inactivation in hepatocellular carcinoma
AU - Lee, Gena
AU - Jeong, Yun Seong
AU - Kim, Do Won
AU - Kwak, Min Jun
AU - Koh, Jiwon
AU - Joo, Eun Wook
AU - Lee, Ju Seog
AU - Kah, Susie
AU - Sim, Yeong Eun
AU - Yim, Sun Young
N1 - Funding Information:
The authors thank Erica Goodoff of the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for editing the manuscript. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07040523) and by the Korea Association for the Study of the Liver and the Korean Liver Foundation and by Korea University Anam Hospital, Seoul, Republic of Korea (Grant no. O1800751) 1Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2Department of Pathology, Seoul National University College of Medicine, Seoul, Korea. 3Department of Gynecology, School of Medicine, Kyung Hee University, Seoul, Korea. 4Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea. 5Department of Internal Medicine, Korea University, College of Medicine, Seoul, Korea
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s12276-018-0174-2
DO - 10.1038/s12276-018-0174-2
M3 - Article
C2 - 30429453
AN - SCOPUS:85056649443
SN - 1226-3613
VL - 50
JO - Experimental and Molecular Medicine
JF - Experimental and Molecular Medicine
IS - 11
M1 - 147
ER -