Potential conflict of interest: KW, SS, SD, TX, ZZ, YW, DP, WJY, PAR, MM and JX are or were employed by Pfizer Inc. KW, SS, SD, YW, and DP own stock in Pfizer.
Genomic landscape of copy number aberrations enables the identification of oncogenic drivers in hepatocellular carcinoma
Article first published online: 1 JUL 2013
Copyright © 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 2, pages 706–717, August 2013
How to Cite
Wang, K., Lim, H. Y., Shi, S., Lee, J., Deng, S., Xie, T., Zhu, Z., Wang, Y., Pocalyko, D., Yang, W. J., Rejto, P. A., Mao, M., Park, C.-K. and Xu, J. (2013), Genomic landscape of copy number aberrations enables the identification of oncogenic drivers in hepatocellular carcinoma. Hepatology, 58: 706–717. doi: 10.1002/hep.26402
Data availability: Both gene expression and SNP genotyping array data have been deposited to Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession numbers GSE36376 and GSE38326, respectively.
- Issue published online: 29 JUL 2013
- Article first published online: 1 JUL 2013
- Accepted manuscript online: 18 MAR 2013 04:05AM EST
- Manuscript Accepted: 13 MAR 2013
- Manuscript Received: 26 SEP 2012
Cancer is a genetic disease with frequent somatic DNA alterations. Studying recurrent copy number aberrations (CNAs) in human cancers would enable the elucidation of disease mechanisms and the prioritization of candidate oncogenic drivers with causal roles in oncogenesis. We have comprehensively and systematically characterized CNAs and the accompanying gene expression changes in tumors and matched nontumor liver tissues from 286 hepatocellular carcinoma (HCC) patients. Our analysis identified 29 recurrently amplified and 22 recurrently deleted regions with a high level of copy number changes. These regions harbor established oncogenes and tumor suppressors, including CCND1 (cyclin D1), MET (hepatocyte growth factor receptor), CDKN2A (cyclin-dependent kinase inhibitor 2A) and CDKN2B (cyclin-dependent kinase inhibitor 2B), as well as many other genes not previously reported to be involved in liver carcinogenesis. Pathway analysis of cis-acting genes in the amplification and deletion peaks implicates alterations of core cancer pathways, including cell-cycle, p53 signaling, phosphoinositide 3-kinase signaling, mitogen-activated protein kinase signaling, Wnt signaling, and transforming growth factor beta signaling, in a large proportion of HCC patients. We further credentialed two candidate driver genes (BCL9 and MTDH) from the recurrent focal amplification peaks and showed that they play a significant role in HCC growth and survival. Conclusion: We have demonstrated that characterizing the CNA landscape in HCC will facilitate the understanding of disease mechanisms and the identification of oncogenic drivers that may serve as potential therapeutic targets for the treatment of this devastating disease. (Hepatology 2013;58:706–717)