Genomic Landscape of Copy Number Aberrations Enables the... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Genomic Landscape of Copy Number Aberrations Enables the Identification of Oncogenic Drivers in Hepatocellular Carcinoma

Wang, Kai1; Lim, Ho Yeong2; Shi, Stephanie3; Lee, Jeeyun2; Deng, Shibing1; Xie, Tao1; Zhu, Zhou1; Wang, Yuli1; Pocalyko, David1,5; Yang, Wei Jennifer1; Rejto, Paul A.1; Mao, Mao1; Park, Cheol-Keun4; Xu, Jiangchun1,6

1_Oncology Research Unit, Pfizer Inc, San Diego, CA,_

2_Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea_

3_External Research Solutions, Pfizer Inc, San Diego, CA,_

4_Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea_

5_Janssen Research & Development, San Diego, CA,_

6_Quanticel Pharmaceuticals, San Diego, CA,_

Received September 26, 2012; accepted March 13, 2013

Address reprint requests to: Kai Wang, Ph.D., Oncology Research Unit, Pfizer Inc., 10646 Science Center Drive, San Diego, CA 92121. E-mail:[email protected]; fax: 858-622-7998; Cheol-Keun Park, M.D., Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, Korea. E-mail:[email protected]; fax: 182-2-34106396; or Jiangchun Xu, E-mail:[email protected]

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.

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.

Abstract

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)