Clinical significance of APOB inactivation in hepatocellular carcinoma

• Published in: Experimental & molecular medicine Vol. 50; no. 11; pp. 1 - 12
• Main Authors: Lee, Gena, Jeong, Yun Seong, Kim, Do Won, Kwak, Min Jun, Koh, Jiwon, Joo, Eun Wook, Lee, Ju-Seog, Kah, Susie, Sim, Yeong-Eun, Yim, Sun Young
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.11.2018; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 45/61; 64/60; 692/53/2422; 692/699/67/1504/1610; 692/699/67/69; Adult; Aged; Animals; APOB gene; Apolipoprotein B; Apolipoproteins B - genetics; Apolipoproteins B - metabolism; Bayesian analysis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; CD44 antigen; Clinical significance; ErbB-2 protein; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genomes; Hep G2 Cells; Hepatocellular carcinoma; Humans; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Medical Biochemistry; Metastases; Mice; Middle Aged; Molecular Medicine; Mutation; p53 Protein; Prognosis; PTEN protein; siRNA; Stem Cells; Transcriptome; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/s12276-018-0174-2

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. Cancer: Spotlighting hidden cancer-causing genes Mutation of a gene with no clear role in tumor development triggers a cascade of reactions that can cause liver cancer. Recent genome-wide analyses searching for genes connected to development of hepatocellular carcinoma, the most common type of liver cancer, have turned up some unexpected genes, such as the fat metabolism gene apolipoprotein A ( APOB ). To discover how APOB is related to liver tumor development, Sun Young Yim at the University of Texas MD Anderson Cancer Center, Houston, USA, and coworkers compared whole-genome profiles from human cancer patients with those of mice, in which cancer-related genetic patterns are better characterized. They found that mutation of APOB was associated with switching on of cancer-promoting genes, and switching off of genes that suppress tumor growth. These results reveal a behind-the-scenes regulator of cancer development.