These authors contributed equally to the study.
Etiology-dependent molecular mechanisms in human hepatocarcinogenesis†
Article first published online: 26 DEC 2007
Copyright © 2007 American Association for the Study of Liver Diseases
Volume 47, Issue 2, pages 511–520, February 2008
How to Cite
Schlaeger, C., Longerich, T., Schiller, C., Bewerunge, P., Mehrabi, A., Toedt, G., Kleeff, J., Ehemann, V., Eils, R., Lichter, P., Schirmacher, P. and Radlwimmer, B. (2008), Etiology-dependent molecular mechanisms in human hepatocarcinogenesis. Hepatology, 47: 511–520. doi: 10.1002/hep.22033
Potential conflict of interest: Nothing to report.
- Issue published online: 26 JAN 2008
- Article first published online: 26 DEC 2007
- Manuscript Accepted: 5 SEP 2007
- Manuscript Received: 3 JUL 2007
- Tumorzentrum Heidelberg/Mannheim
- Bundesministerium für Bildung und Forschung. Grant Numbers: 01GS0460, 01GR0450
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is characterized by aggressive tumor behavior coupled with poor prognosis. Various etiologies have been linked to HCC development, most prominently chronic hepatitis B and C virus infections as well as chronic alcohol consumption. In approximately 10% of HCCs, the etiology remains cryptic; however, recent epidemiological data suggest that most of these cryptogenic HCCs develop due to nonalcoholic steatohepatitis. To identify etiology-dependent DNA copy number aberrations and genes relevant to hepatocarcinogenesis, we performed array-based comparative genomic hybridization of 63 HCCs of well-defined etiology and 4 HCC cell lines followed by gene expression profiling and functional analyses of candidate genes. For a 10-megabase chromosome region on 8q24, we observed etiology-dependent copy number gains and MYC overexpression in viral and alcohol-related HCCs, resulting in up-regulation of MYC target genes. Cryptogenic HCCs showed neither 8q24 gains, nor MYC overexpression, nor target gene activation, suggesting that tumors of this etiology develop by way of a distinct MYC-independent pathomechanism. Furthermore, we detected several etiology-independent small chromosome aberrations, including amplification of MDM4 on 1q32.1 and frequent gains of EEF1A2 on 20q13.33. Both genes were overexpressed in approximately half the HCCs examined, and gene silencing reduced cell viability as well as proliferation and increased apoptosis rates in HCC cell lines. Conclusion: Our findings suggest that MDM4 and EEF1A2 act as etiology-independent oncogenes in a significant percentage of HCCs. (HEPATOLOGY 2008.)