Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Authors: Adrian Ally, Miruna Balasundaram, Rebecca Carlsen, Eric Chuah, Amanda Clarke, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Dorothy Cheung, Tina Wong, Denise Brooks, A. Gordon Robertson, Reanne Bowlby, Karen Mungall, Sara Sadeghi, Xi Liu, Kyle R. Covington, Eve Shinbrot, David A. Wheeler, Richard A. Gibbs, Lawrence A. Donehower, Linghua Wang, Jay Bowen, Julie M. Gastier‐Foster, Mark Gerken, Carmen Helsel, Kristen Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Stacey Gabriel, Matthew Meyerson, Carrie Cibulskis, Bradley A. Murray, Juliann Shih, Rameen Beroukhim, Andrew D. Cherniack, Steven E. Schumacher, Gordon Saksena, Chandra Sekhar Pedamallu, Lynda Chin, Gad Getz, Michael S. Noble, Hailei Zhang, David I. Heiman, Juok Cho, Nils Gehlenborg, Gordon Saksena, Douglas Voet, Pei Lin, Scott Frazer, Timothy Defreitas, Sam Meier, Michael S. Lawrence, Jaegil Kim, Chad J. Creighton, Donna M. Muzny, HarshaVardhan Doddapaneni, Hai Hu, Min Wang, Donna Morton, Viktoriya Korchina, Yi Han, Huyen Dinh, Lora Lewis, Michelle Bellair, Xiuping Liu, Jireh Santibanez, Robert Glenn, Sandra Lee, Walker Hale, Joel S. Parker, Matthew D. Wilkerson, D. Neil Hayes, Sheila M. Reynolds, Ilya Shmulevich, Wei Zhang, Yuexin Liu, Lisa Iype, Hala R. Makhlouf, Michael Torbenson, Sanjay Kakar, Matthew M. Yeh, Dhanpat Jain, David E. Kleiner, Dhanpat Jain, Renumathy Dhanasekaran, Hashem B. El‐Serag, Sun Young Yim, John N. Weinstein, Lopa Mishra, Jianping Zhang, Rehan Akbani, Shiyun Ling, Zhenlin Ju, Xiaoping Su, Apurva M. Hegde, Gordon B. Mills, Yiling Lu, Jian Chen, Ju‐Seog Lee, Bo Hwa Sohn, Jae‐Jun Shim, Pan Tong, Hiroyuki Aburatani, Shogo Yamamoto, Kenji Tatsuno, Wei Li, Zheng Xia, Nicolas Stransky, Eric Seiser, Federico Innocenti, Jianjiong Gao, Ritika Kundra, Hongxin Zhang, Zachary Heins, Angelica Ochoa, Chris Sander, Marc Ladanyi, Ronglai Shen, Arshi Arora, Francisco Sánchez-Vega, Nikolaus Schultz, Katayoon Kasaian, Amie Radenbaugh, Karl‐Dimiter Bissig, David D. Moore, Yasushi Totoki, Hiromi Nakamura, Tatsuhiro Shibata, Christina Yau, Kiley Graim, Joshua M. Stuart, David Haussler, Betty L. Slagle, Akinyemi I. Ojesina, Panagiotis Katsonis, Amanda Koire, Olivier Lichtarge, Teng‐Kuei Hsu, Martin L. Ferguson, John A. Demchok, Ina Felau, Margi Sheth, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan Zhang, Carolyn M. Hutter, Heidi J. Sofia, Roel G.W. Verhaak, Siyuan Zheng, Frederick Lang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Ye Wu, Rashi Naresh, Todd Pihl, Charlie Sun, Yunhu Wan, Christopher C. Benz, Amy H. Perou, Leigh B. Thorne, Lori Boice, Mei Huang, W. Kimryn Rathmell, Houtan Noushmehr, Fabiano Pinto Saggioro, Daniela Pretti da Cunha Tirapelli, Carlos Gilberto Carlotti, Ênio David Mente, Orlando de Castro Silva, Felipe Amstalden Trevisan, Koo Jeong Kang, Keun Soo Ahn, Nasra H. Giama, Catherine D. Moser, Thomas J. Giordano, Michelle Vinco, Theodore H. Welling, Daniel Crain, Erin Curley, Johanna Gardner, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Robin Kate Kelley, Joong‐Won Park, Vishal S. Chandan, Lewis R. Roberts, Oliver F. Bathe, Curt H. Hagedorn, J. Todd Auman, Daniel R. O’Brien, Jean‐Pierre Kocher, Corbin D. Jones, Piotr A. Mieczkowski, Charles M. Perou, Tara Skelly, Donghui Tan, Umadevi Veluvolu, Saianand Balu, Tom Bodenheimer, Alan P. Hoyle, Stuart R. Jefferys, Shaowu Meng, Lisle E. Mose, Yan Shi, Janae V. Simons, Matthew G. Soloway, Jeffrey Roach, Katherine A. Hoadley, Stephen B. Baylin, Hui Shen, Toshinori Hinoue, Moiz S. Bootwalla, David Van Den Berg, Daniel J. Weisenberger, Phillip H. Lai, Andrea Holbrook, Mario Berríos, Peter W. Laird - Cell 2017 cited by 2,591

Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.