Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

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 & 219 others Denise Brooks, A. Gordon Robertson, Reanne Bowlby, Karen Mungall, Sara Sadeghi, Liu Xi, Kyle 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 M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Stacey B. 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 Noble, Hailei Zhang, David Heiman, Juok Cho, Nils Gehlenborg, Gordon Saksena, Douglas Voet, Pei Lin, Scott Frazer, Timothy Defreitas, Sam Meier, Michael Lawrence, Jaegil Kim, Chad J. Creighton, Donna Muzny, Harsha Vardhan Doddapaneni, Jianhong 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 Makhlouf, Michael S. 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 Sanchez-Vega, Nikolaus Schultz, Katayoon Kasaian, Amie Radenbaugh, Karl Dimiter Bissig, David D. Moore, Yasushi Totoki, Hiromi Nakamura, Tatsuhiro Shibata, Christina Yau, Kiley Graim, Josh 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 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 Junior, Enio 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 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 A. 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 J. Van Den Berg, Daniel J. Weisenberger, Phillip H. Lai, Andrea Holbrook, Mario Berrios, Peter W. Laird,

Research output: Research - peer-reviewArticle

  • 7 Citations

Abstract

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.

LanguageEnglish (US)
Pages1327-1341.e23
JournalCell
Volume169
Issue number7
DOIs
StatePublished - Jun 15 2017

Fingerprint

Genes
DNA
Hepatocellular Carcinoma
MicroRNAs
Gene expression
Liver
RNA
Proteins
DNA Methylation
Proteomics
DNA Sequence Analysis
Mutation
Therapeutics
Exome
p53 Genes
Liver Neoplasms
Transcriptome
Cluster Analysis
Down-Regulation
Mortality

Keywords

  • cancer subtyping
  • expression profile
  • hepatocellular carcinoma
  • IDH1/2
  • metabolic reprogramming
  • promoter hypermethylation
  • significantly mutated genes
  • sonic hedgehog signaling
  • stem cell phenotype
  • TP53

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ally, A., Balasundaram, M., Carlsen, R., Chuah, E., Clarke, A., Dhalla, N., ... The Cancer Genome Atlas Research Network (2017). Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell, 169(7), 1327-1341.e23. DOI: 10.1016/j.cell.2017.05.046

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

In: Cell, Vol. 169, No. 7, 15.06.2017, p. 1327-1341.e23.

Research output: Research - peer-reviewArticle

Ally, A, Balasundaram, M, Carlsen, R, Chuah, E, Clarke, A, Dhalla, N, Holt, RA, Jones, SJM, Lee, D, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Cheung, D, Wong, T, Brooks, D, Robertson, AG, Bowlby, R, Mungall, K, Sadeghi, S, Xi, L, Covington, K, Shinbrot, E, Wheeler, DA, Gibbs, RA, Donehower, LA, Wang, L, Bowen, J, Gastier-Foster, JM, Gerken, M, Helsel, C, Leraas, KM, Lichtenberg, TM, Ramirez, NC, Wise, L, Zmuda, E, Gabriel, SB, Meyerson, M, Cibulskis, C, Murray, BA, Shih, J, Beroukhim, R, Cherniack, AD, Schumacher, SE, Saksena, G, Pedamallu, CS, Chin, L, Getz, G, Noble, M, Zhang, H, Heiman, D, Cho, J, Gehlenborg, N, Saksena, G, Voet, D, Lin, P, Frazer, S, Defreitas, T, Meier, S, Lawrence, M, Kim, J, Creighton, CJ, Muzny, D, Doddapaneni, HV, Hu, J, Wang, M, Morton, D, Korchina, V, Han, Y, Dinh, H, Lewis, L, Bellair, M, Liu, X, Santibanez, J, Glenn, R, Lee, S, Hale, W, Parker, JS, Wilkerson, MD, Hayes, DN, Reynolds, SM, Shmulevich, I, Zhang, W, Liu, Y, Iype, L, Makhlouf, H, Torbenson, MS, Kakar, S, Yeh, MM, Jain, D, Kleiner, DE, Jain, D, Dhanasekaran, R, El-Serag, HB, Yim, SY, Weinstein, JN, Mishra, L, Zhang, J, Akbani, R, Ling, S, Ju, Z, Su, X, Hegde, AM, Mills, GB, Lu, Y, Chen, J, Lee, JS, Sohn, BH, Shim, JJ, Tong, P, Aburatani, H, Yamamoto, S, Tatsuno, K, Li, W, Xia, Z, Stransky, N, Seiser, E, Innocenti, F, Gao, J, Kundra, R, Zhang, H, Heins, Z, Ochoa, A, Sander, C, Ladanyi, M, Shen, R, Arora, A, Sanchez-Vega, F, Schultz, N, Kasaian, K, Radenbaugh, A, Bissig, KD, Moore, DD, Totoki, Y, Nakamura, H, Shibata, T, Yau, C, Graim, K, Stuart, J, Haussler, D, Slagle, BL, Ojesina, AI, Katsonis, P, Koire, A, Lichtarge, O, Hsu, TK, Ferguson, ML, Demchok, JA, Felau, I, Sheth, M, Tarnuzzer, R, Wang, Z, Yang, L, Zenklusen, JC, Zhang, J, Hutter, CM, Sofia, HJ, Verhaak, RGW, Zheng, S, Lang, F, Chudamani, S, Liu, J, Lolla, L, Wu, Y, Naresh, R, Pihl, T, Sun, C, Wan, Y, Benz, C, Perou, AH, Thorne, LB, Boice, L, Huang, M, Rathmell, WK, Noushmehr, H, Saggioro, FP, Tirapelli, DPDC, Junior, CGC, Mente, ED, Silva, ODC, Trevisan, FA, Kang, KJ, Ahn, KS, Giama, NH, Moser, CD, Giordano, TJ, Vinco, M, Welling, TH, Crain, D, Curley, E, Gardner, J, Mallery, D, Morris, S, Paulauskis, J, Penny, R, Shelton, C, Shelton, T, Kelley, R, Park, JW, Chandan, VS, Roberts, LR, Bathe, OF, Hagedorn, CH, Auman, JT, O'Brien, DR, Kocher, JPA, Jones, CD, Mieczkowski, PA, Perou, CM, Skelly, T, Tan, D, Veluvolu, U, Balu, S, Bodenheimer, T, Hoyle, AP, Jefferys, SR, Meng, S, Mose, LE, Shi, Y, Simons, JV, Soloway, MG, Roach, J, Hoadley, KA, Baylin, SB, Shen, H, Hinoue, T, Bootwalla, MS, Van Den Berg, DJ, Weisenberger, DJ, Lai, PH, Holbrook, A, Berrios, M, Laird, PW & The Cancer Genome Atlas Research Network 2017, 'Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma' Cell, vol 169, no. 7, pp. 1327-1341.e23. DOI: 10.1016/j.cell.2017.05.046
Ally A, Balasundaram M, Carlsen R, Chuah E, Clarke A, Dhalla N et al. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell. 2017 Jun 15;169(7):1327-1341.e23. Available from, DOI: 10.1016/j.cell.2017.05.046
Ally, Adrian ; Balasundaram, Miruna ; Carlsen, Rebecca ; Chuah, Eric ; Clarke, Amanda ; Dhalla, Noreen ; Holt, Robert A. ; Jones, Steven J.M. ; Lee, Darlene ; Ma, Yussanne ; Marra, Marco A. ; Mayo, Michael ; Moore, Richard A. ; Mungall, Andrew J. ; Schein, Jacqueline E. ; Sipahimalani, Payal ; Tam, Angela ; Thiessen, Nina ; Cheung, Dorothy ; Wong, Tina ; Brooks, Denise ; Robertson, A. Gordon ; Bowlby, Reanne ; Mungall, Karen ; Sadeghi, Sara ; Xi, Liu ; Covington, Kyle ; Shinbrot, Eve ; Wheeler, David A. ; Gibbs, Richard A. ; Donehower, Lawrence A. ; Wang, Linghua ; Bowen, Jay ; Gastier-Foster, Julie M. ; Gerken, Mark ; Helsel, Carmen ; Leraas, Kristen M. ; Lichtenberg, Tara M. ; Ramirez, Nilsa C. ; Wise, Lisa ; Zmuda, Erik ; Gabriel, Stacey B. ; Meyerson, Matthew ; Cibulskis, Carrie ; Murray, Bradley A. ; Shih, Juliann ; Beroukhim, Rameen ; Cherniack, Andrew D. ; Schumacher, Steven E. ; Saksena, Gordon ; Pedamallu, Chandra Sekhar ; Chin, Lynda ; Getz, Gad ; Noble, Michael ; Zhang, Hailei ; Heiman, David ; Cho, Juok ; Gehlenborg, Nils ; Saksena, Gordon ; Voet, Douglas ; Lin, Pei ; Frazer, Scott ; Defreitas, Timothy ; Meier, Sam ; Lawrence, Michael ; Kim, Jaegil ; Creighton, Chad J. ; Muzny, Donna ; Doddapaneni, Harsha Vardhan ; Hu, Jianhong ; Wang, Min ; Morton, Donna ; Korchina, Viktoriya ; Han, Yi ; Dinh, Huyen ; Lewis, Lora ; Bellair, Michelle ; Liu, Xiuping ; Santibanez, Jireh ; Glenn, Robert ; Lee, Sandra ; Hale, Walker ; Parker, Joel S. ; Wilkerson, Matthew D. ; Hayes, D. Neil ; Reynolds, Sheila M. ; Shmulevich, Ilya ; Zhang, Wei ; Liu, Yuexin ; Iype, Lisa ; Makhlouf, Hala ; Torbenson, Michael S. ; Kakar, Sanjay ; Yeh, Matthew M. ; Jain, Dhanpat ; Kleiner, David E. ; Jain, Dhanpat ; Dhanasekaran, Renumathy ; El-Serag, Hashem B. ; Yim, Sun Young ; Weinstein, John N. ; Mishra, Lopa ; Zhang, Jianping ; Akbani, Rehan ; Ling, Shiyun ; Ju, Zhenlin ; Su, Xiaoping ; Hegde, Apurva M. ; Mills, Gordon B. ; Lu, Yiling ; Chen, Jian ; Lee, Ju Seog ; Sohn, Bo Hwa ; Shim, Jae Jun ; Tong, Pan ; Aburatani, Hiroyuki ; Yamamoto, Shogo ; Tatsuno, Kenji ; Li, Wei ; Xia, Zheng ; Stransky, Nicolas ; Seiser, Eric ; Innocenti, Federico ; Gao, Jianjiong ; Kundra, Ritika ; Zhang, Hongxin ; Heins, Zachary ; Ochoa, Angelica ; Sander, Chris ; Ladanyi, Marc ; Shen, Ronglai ; Arora, Arshi ; Sanchez-Vega, Francisco ; Schultz, Nikolaus ; Kasaian, Katayoon ; Radenbaugh, Amie ; Bissig, Karl Dimiter ; Moore, David D. ; Totoki, Yasushi ; Nakamura, Hiromi ; Shibata, Tatsuhiro ; Yau, Christina ; Graim, Kiley ; Stuart, Josh ; Haussler, David ; Slagle, Betty L. ; Ojesina, Akinyemi I. ; Katsonis, Panagiotis ; Koire, Amanda ; Lichtarge, Olivier ; Hsu, Teng Kuei ; Ferguson, Martin L. ; Demchok, John A. ; Felau, Ina ; Sheth, Margi ; Tarnuzzer, Roy ; Wang, Zhining ; Yang, Liming ; Zenklusen, Jean C. ; Zhang, Jiashan ; Hutter, Carolyn M. ; Sofia, Heidi J. ; Verhaak, Roel G.W. ; Zheng, Siyuan ; Lang, Frederick ; Chudamani, Sudha ; Liu, Jia ; Lolla, Laxmi ; Wu, Ye ; Naresh, Rashi ; Pihl, Todd ; Sun, Charlie ; Wan, Yunhu ; Benz, Christopher ; Perou, Amy H. ; Thorne, Leigh B. ; Boice, Lori ; Huang, Mei ; Rathmell, W. Kimryn ; Noushmehr, Houtan ; Saggioro, Fabiano Pinto ; Tirapelli, Daniela Pretti da Cunha ; Junior, Carlos Gilberto Carlotti ; Mente, Enio David ; Silva, Orlando de Castro ; Trevisan, Felipe Amstalden ; Kang, Koo Jeong ; Ahn, Keun Soo ; Giama, Nasra H. ; Moser, Catherine D. ; Giordano, Thomas J. ; Vinco, Michelle ; Welling, Theodore H. ; Crain, Daniel ; Curley, Erin ; Gardner, Johanna ; Mallery, David ; Morris, Scott ; Paulauskis, Joseph ; Penny, Robert ; Shelton, Candace ; Shelton, Troy ; Kelley, Robin ; Park, Joong Won ; Chandan, Vishal S. ; Roberts, Lewis R. ; Bathe, Oliver F. ; Hagedorn, Curt H. ; Auman, J. Todd ; O'Brien, Daniel R. ; Kocher, Jean Pierre A. ; Jones, Corbin D. ; Mieczkowski, Piotr A. ; Perou, Charles M. ; Skelly, Tara ; Tan, Donghui ; Veluvolu, Umadevi ; Balu, Saianand ; Bodenheimer, Tom ; Hoyle, Alan P. ; Jefferys, Stuart R. ; Meng, Shaowu ; Mose, Lisle E. ; Shi, Yan ; Simons, Janae V. ; Soloway, Matthew G. ; Roach, Jeffrey ; Hoadley, Katherine A. ; Baylin, Stephen B. ; Shen, Hui ; Hinoue, Toshinori ; Bootwalla, Moiz S. ; Van Den Berg, David J. ; Weisenberger, Daniel J. ; Lai, Phillip H. ; Holbrook, Andrea ; Berrios, Mario ; Laird, Peter W. ; The Cancer Genome Atlas Research Network. / Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. In: Cell. 2017 ; Vol. 169, No. 7. pp. 1327-1341.e23
@article{c2a639645e144319bb482ae5f5c62335,
title = "Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma",
abstract = "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.",
keywords = "cancer subtyping, expression profile, hepatocellular carcinoma, IDH1/2, metabolic reprogramming, promoter hypermethylation, significantly mutated genes, sonic hedgehog signaling, stem cell phenotype, TP53",
author = "Adrian Ally and Miruna Balasundaram and Rebecca Carlsen and Eric Chuah and Amanda Clarke and Noreen Dhalla and Holt, {Robert A.} and Jones, {Steven J.M.} and Darlene Lee and Yussanne Ma and Marra, {Marco A.} and Michael Mayo and Moore, {Richard A.} and Mungall, {Andrew J.} and Schein, {Jacqueline E.} and Payal Sipahimalani and Angela Tam and Nina Thiessen and Dorothy Cheung and Tina Wong and Denise Brooks and Robertson, {A. Gordon} and Reanne Bowlby and Karen Mungall and Sara Sadeghi and Liu Xi and Kyle Covington and Eve Shinbrot and Wheeler, {David A.} and Gibbs, {Richard A.} and Donehower, {Lawrence A.} and Linghua Wang and Jay Bowen and Gastier-Foster, {Julie M.} and Mark Gerken and Carmen Helsel and Leraas, {Kristen M.} and Lichtenberg, {Tara M.} and Ramirez, {Nilsa C.} and Lisa Wise and Erik Zmuda and Gabriel, {Stacey B.} and Matthew Meyerson and Carrie Cibulskis and Murray, {Bradley A.} and Juliann Shih and Rameen Beroukhim and Cherniack, {Andrew D.} and Schumacher, {Steven E.} and Gordon Saksena and Pedamallu, {Chandra Sekhar} and Lynda Chin and Gad Getz and Michael Noble and Hailei Zhang and David Heiman and Juok Cho and Nils Gehlenborg and Gordon Saksena and Douglas Voet and Pei Lin and Scott Frazer and Timothy Defreitas and Sam Meier and Michael Lawrence and Jaegil Kim and Creighton, {Chad J.} and Donna Muzny and Doddapaneni, {Harsha Vardhan} and Jianhong Hu and Min Wang and Donna Morton and Viktoriya Korchina and Yi Han and Huyen Dinh and Lora Lewis and Michelle Bellair and Xiuping Liu and Jireh Santibanez and Robert Glenn and Sandra Lee and Walker Hale and Parker, {Joel S.} and Wilkerson, {Matthew D.} and Hayes, {D. Neil} and Reynolds, {Sheila M.} and Ilya Shmulevich and Wei Zhang and Yuexin Liu and Lisa Iype and Hala Makhlouf and Torbenson, {Michael S.} and Sanjay Kakar and Yeh, {Matthew M.} and Dhanpat Jain and Kleiner, {David E.} and Dhanpat Jain and Renumathy Dhanasekaran and El-Serag, {Hashem B.} and Yim, {Sun Young} and Weinstein, {John N.} and Lopa Mishra and Jianping Zhang and Rehan Akbani and Shiyun Ling and Zhenlin Ju and Xiaoping Su and Hegde, {Apurva M.} and Mills, {Gordon B.} and Yiling Lu and Jian Chen and Lee, {Ju Seog} and Sohn, {Bo Hwa} and Shim, {Jae Jun} and Pan Tong and Hiroyuki Aburatani and Shogo Yamamoto and Kenji Tatsuno and Wei Li and Zheng Xia and Nicolas Stransky and Eric Seiser and Federico Innocenti and Jianjiong Gao and Ritika Kundra and Hongxin Zhang and Zachary Heins and Angelica Ochoa and Chris Sander and Marc Ladanyi and Ronglai Shen and Arshi Arora and Francisco Sanchez-Vega and Nikolaus Schultz and Katayoon Kasaian and Amie Radenbaugh and Bissig, {Karl Dimiter} and Moore, {David D.} and Yasushi Totoki and Hiromi Nakamura and Tatsuhiro Shibata and Christina Yau and Kiley Graim and Josh Stuart and David Haussler and Slagle, {Betty L.} and Ojesina, {Akinyemi I.} and Panagiotis Katsonis and Amanda Koire and Olivier Lichtarge and Hsu, {Teng Kuei} and Ferguson, {Martin L.} and Demchok, {John A.} and Ina Felau and Margi Sheth and Roy Tarnuzzer and Zhining Wang and Liming Yang and Zenklusen, {Jean C.} and Jiashan Zhang and Hutter, {Carolyn M.} and Sofia, {Heidi J.} and Verhaak, {Roel G.W.} and Siyuan Zheng and Frederick Lang and Sudha Chudamani and Jia Liu and Laxmi Lolla and Ye Wu and Rashi Naresh and Todd Pihl and Charlie Sun and Yunhu Wan and Christopher Benz and Perou, {Amy H.} and Thorne, {Leigh B.} and Lori Boice and Mei Huang and Rathmell, {W. Kimryn} and Houtan Noushmehr and Saggioro, {Fabiano Pinto} and Tirapelli, {Daniela Pretti da Cunha} and Junior, {Carlos Gilberto Carlotti} and Mente, {Enio David} and Silva, {Orlando de Castro} and Trevisan, {Felipe Amstalden} and Kang, {Koo Jeong} and Ahn, {Keun Soo} and Giama, {Nasra H.} and Moser, {Catherine D.} and Giordano, {Thomas J.} and Michelle Vinco and Welling, {Theodore H.} and Daniel Crain and Erin Curley and Johanna Gardner and David Mallery and Scott Morris and Joseph Paulauskis and Robert Penny and Candace Shelton and Troy Shelton and Robin Kelley and Park, {Joong Won} and Chandan, {Vishal S.} and Roberts, {Lewis R.} and Bathe, {Oliver F.} and Hagedorn, {Curt H.} and Auman, {J. Todd} and O'Brien, {Daniel R.} and Kocher, {Jean Pierre A.} and Jones, {Corbin D.} and Mieczkowski, {Piotr A.} and Perou, {Charles M.} and Tara Skelly and Donghui Tan and Umadevi Veluvolu and Saianand Balu and Tom Bodenheimer and Hoyle, {Alan P.} and Jefferys, {Stuart R.} and Shaowu Meng and Mose, {Lisle E.} and Yan Shi and Simons, {Janae V.} and Soloway, {Matthew G.} and Jeffrey Roach and Hoadley, {Katherine A.} and Baylin, {Stephen B.} and Hui Shen and Toshinori Hinoue and Bootwalla, {Moiz S.} and {Van Den Berg}, {David J.} and Weisenberger, {Daniel J.} and Lai, {Phillip H.} and Andrea Holbrook and Mario Berrios and Laird, {Peter W.} and {The Cancer Genome Atlas Research Network}",
year = "2017",
month = "6",
doi = "10.1016/j.cell.2017.05.046",
volume = "169",
pages = "1327--1341.e23",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "7",

}

TY - JOUR

T1 - Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

AU - Ally,Adrian

AU - Balasundaram,Miruna

AU - Carlsen,Rebecca

AU - Chuah,Eric

AU - Clarke,Amanda

AU - Dhalla,Noreen

AU - Holt,Robert A.

AU - Jones,Steven J.M.

AU - Lee,Darlene

AU - Ma,Yussanne

AU - Marra,Marco A.

AU - Mayo,Michael

AU - Moore,Richard A.

AU - Mungall,Andrew J.

AU - Schein,Jacqueline E.

AU - Sipahimalani,Payal

AU - Tam,Angela

AU - Thiessen,Nina

AU - Cheung,Dorothy

AU - Wong,Tina

AU - Brooks,Denise

AU - Robertson,A. Gordon

AU - Bowlby,Reanne

AU - Mungall,Karen

AU - Sadeghi,Sara

AU - Xi,Liu

AU - Covington,Kyle

AU - Shinbrot,Eve

AU - Wheeler,David A.

AU - Gibbs,Richard A.

AU - Donehower,Lawrence A.

AU - Wang,Linghua

AU - Bowen,Jay

AU - Gastier-Foster,Julie M.

AU - Gerken,Mark

AU - Helsel,Carmen

AU - Leraas,Kristen M.

AU - Lichtenberg,Tara M.

AU - Ramirez,Nilsa C.

AU - Wise,Lisa

AU - Zmuda,Erik

AU - Gabriel,Stacey B.

AU - Meyerson,Matthew

AU - Cibulskis,Carrie

AU - Murray,Bradley A.

AU - Shih,Juliann

AU - Beroukhim,Rameen

AU - Cherniack,Andrew D.

AU - Schumacher,Steven E.

AU - Saksena,Gordon

AU - Pedamallu,Chandra Sekhar

AU - Chin,Lynda

AU - Getz,Gad

AU - Noble,Michael

AU - Zhang,Hailei

AU - Heiman,David

AU - Cho,Juok

AU - Gehlenborg,Nils

AU - Saksena,Gordon

AU - Voet,Douglas

AU - Lin,Pei

AU - Frazer,Scott

AU - Defreitas,Timothy

AU - Meier,Sam

AU - Lawrence,Michael

AU - Kim,Jaegil

AU - Creighton,Chad J.

AU - Muzny,Donna

AU - Doddapaneni,Harsha Vardhan

AU - Hu,Jianhong

AU - Wang,Min

AU - Morton,Donna

AU - Korchina,Viktoriya

AU - Han,Yi

AU - Dinh,Huyen

AU - Lewis,Lora

AU - Bellair,Michelle

AU - Liu,Xiuping

AU - Santibanez,Jireh

AU - Glenn,Robert

AU - Lee,Sandra

AU - Hale,Walker

AU - Parker,Joel S.

AU - Wilkerson,Matthew D.

AU - Hayes,D. Neil

AU - Reynolds,Sheila M.

AU - Shmulevich,Ilya

AU - Zhang,Wei

AU - Liu,Yuexin

AU - Iype,Lisa

AU - Makhlouf,Hala

AU - Torbenson,Michael S.

AU - Kakar,Sanjay

AU - Yeh,Matthew M.

AU - Jain,Dhanpat

AU - Kleiner,David E.

AU - Jain,Dhanpat

AU - Dhanasekaran,Renumathy

AU - El-Serag,Hashem B.

AU - Yim,Sun Young

AU - Weinstein,John N.

AU - Mishra,Lopa

AU - Zhang,Jianping

AU - Akbani,Rehan

AU - Ling,Shiyun

AU - Ju,Zhenlin

AU - Su,Xiaoping

AU - Hegde,Apurva M.

AU - Mills,Gordon B.

AU - Lu,Yiling

AU - Chen,Jian

AU - Lee,Ju Seog

AU - Sohn,Bo Hwa

AU - Shim,Jae Jun

AU - Tong,Pan

AU - Aburatani,Hiroyuki

AU - Yamamoto,Shogo

AU - Tatsuno,Kenji

AU - Li,Wei

AU - Xia,Zheng

AU - Stransky,Nicolas

AU - Seiser,Eric

AU - Innocenti,Federico

AU - Gao,Jianjiong

AU - Kundra,Ritika

AU - Zhang,Hongxin

AU - Heins,Zachary

AU - Ochoa,Angelica

AU - Sander,Chris

AU - Ladanyi,Marc

AU - Shen,Ronglai

AU - Arora,Arshi

AU - Sanchez-Vega,Francisco

AU - Schultz,Nikolaus

AU - Kasaian,Katayoon

AU - Radenbaugh,Amie

AU - Bissig,Karl Dimiter

AU - Moore,David D.

AU - Totoki,Yasushi

AU - Nakamura,Hiromi

AU - Shibata,Tatsuhiro

AU - Yau,Christina

AU - Graim,Kiley

AU - Stuart,Josh

AU - Haussler,David

AU - Slagle,Betty L.

AU - Ojesina,Akinyemi I.

AU - Katsonis,Panagiotis

AU - Koire,Amanda

AU - Lichtarge,Olivier

AU - Hsu,Teng Kuei

AU - Ferguson,Martin L.

AU - Demchok,John A.

AU - Felau,Ina

AU - Sheth,Margi

AU - Tarnuzzer,Roy

AU - Wang,Zhining

AU - Yang,Liming

AU - Zenklusen,Jean C.

AU - Zhang,Jiashan

AU - Hutter,Carolyn M.

AU - Sofia,Heidi J.

AU - Verhaak,Roel G.W.

AU - Zheng,Siyuan

AU - Lang,Frederick

AU - Chudamani,Sudha

AU - Liu,Jia

AU - Lolla,Laxmi

AU - Wu,Ye

AU - Naresh,Rashi

AU - Pihl,Todd

AU - Sun,Charlie

AU - Wan,Yunhu

AU - Benz,Christopher

AU - Perou,Amy H.

AU - Thorne,Leigh B.

AU - Boice,Lori

AU - Huang,Mei

AU - Rathmell,W. Kimryn

AU - Noushmehr,Houtan

AU - Saggioro,Fabiano Pinto

AU - Tirapelli,Daniela Pretti da Cunha

AU - Junior,Carlos Gilberto Carlotti

AU - Mente,Enio David

AU - Silva,Orlando de Castro

AU - Trevisan,Felipe Amstalden

AU - Kang,Koo Jeong

AU - Ahn,Keun Soo

AU - Giama,Nasra H.

AU - Moser,Catherine D.

AU - Giordano,Thomas J.

AU - Vinco,Michelle

AU - Welling,Theodore H.

AU - Crain,Daniel

AU - Curley,Erin

AU - Gardner,Johanna

AU - Mallery,David

AU - Morris,Scott

AU - Paulauskis,Joseph

AU - Penny,Robert

AU - Shelton,Candace

AU - Shelton,Troy

AU - Kelley,Robin

AU - Park,Joong Won

AU - Chandan,Vishal S.

AU - Roberts,Lewis R.

AU - Bathe,Oliver F.

AU - Hagedorn,Curt H.

AU - Auman,J. Todd

AU - O'Brien,Daniel R.

AU - Kocher,Jean Pierre A.

AU - Jones,Corbin D.

AU - Mieczkowski,Piotr A.

AU - Perou,Charles M.

AU - Skelly,Tara

AU - Tan,Donghui

AU - Veluvolu,Umadevi

AU - Balu,Saianand

AU - Bodenheimer,Tom

AU - Hoyle,Alan P.

AU - Jefferys,Stuart R.

AU - Meng,Shaowu

AU - Mose,Lisle E.

AU - Shi,Yan

AU - Simons,Janae V.

AU - Soloway,Matthew G.

AU - Roach,Jeffrey

AU - Hoadley,Katherine A.

AU - Baylin,Stephen B.

AU - Shen,Hui

AU - Hinoue,Toshinori

AU - Bootwalla,Moiz S.

AU - Van Den Berg,David J.

AU - Weisenberger,Daniel J.

AU - Lai,Phillip H.

AU - Holbrook,Andrea

AU - Berrios,Mario

AU - Laird,Peter W.

AU - The Cancer Genome Atlas Research Network

PY - 2017/6/15

Y1 - 2017/6/15

N2 - 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.

AB - 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.

KW - cancer subtyping

KW - expression profile

KW - hepatocellular carcinoma

KW - IDH1/2

KW - metabolic reprogramming

KW - promoter hypermethylation

KW - significantly mutated genes

KW - sonic hedgehog signaling

KW - stem cell phenotype

KW - TP53

UR - http://www.scopus.com/inward/record.url?scp=85020833799&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020833799&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.05.046

DO - 10.1016/j.cell.2017.05.046

M3 - Article

VL - 169

SP - 1327-1341.e23

JO - Cell

T2 - Cell

JF - Cell

SN - 0092-8674

IS - 7

ER -