Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer
Yumeng Wang(The University of Texas MD Anderson Cancer Center), Xiaoyan Xu(The University of Texas MD Anderson Cancer Center), Dejan Maglic(Boston Children's Hospital), Michael T. Dill(Boston Children's Hospital), Kamalika Mojumdar(The University of Texas MD Anderson Cancer Center), Patrick Kwok‐Shing Ng(The University of Texas MD Anderson Cancer Center), Kang Jin Jeong(The University of Texas MD Anderson Cancer Center), Yiu Huen Tsang(Baylor College of Medicine), Daniela Moreno(Baylor College of Medicine), Venkata Hemanjani Bhavana(Baylor College of Medicine), Xinxin Peng(The University of Texas MD Anderson Cancer Center), Zhongqi Ge(The University of Texas MD Anderson Cancer Center), Hu Chen(The University of Texas MD Anderson Cancer Center), Jun Li(The University of Texas MD Anderson Cancer Center), Zhongyuan Chen(The University of Texas MD Anderson Cancer Center), Huiwen Zhang(The University of Texas Health Science Center at Houston), Leng Han(The University of Texas Health Science Center at Houston), Di Du(The University of Texas MD Anderson Cancer Center), Chad J. Creighton(Baylor College of Medicine), Gordon B. Mills(The University of Texas MD Anderson Cancer Center), Rory Johnson(Boston Children's Hospital), John A. Demchok(The University of Texas MD Anderson Cancer Center), Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen(The University of Texas MD Anderson Cancer Center), Jiashan Zhang, Sudha Chudamani, Jia Liu(The University of Texas Health Science Center at Houston), Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho(The University of Texas MD Anderson Cancer Center), Timothy Defreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang(The University of Texas MD Anderson Cancer Center), Brady Bernard, Nyasha Chambwe(The University of Texas Health Science Center at Houston), Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael B. Miller, Sheila M. Reynolds, Ilya Shmulevich(Boston Children's Hospital), Vésteinn Thórsson, Wei Zhang, Rehan Akbani, Bradley M. Broom(The University of Texas Health Science Center at Houston), Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut(The University of Texas MD Anderson Cancer Center), Jun Li(The University of Texas MD Anderson Cancer Center), Han Liang(The University of Texas MD Anderson Cancer Center), Shiyun Ling(The University of Texas MD Anderson Cancer Center), Wenbin Liu(The University of Texas MD Anderson Cancer Center), Yiling Lu, Gordon B. Mills(The University of Texas MD Anderson Cancer Center), Kwok-Shing Ng, Arvind Rao(The University of Texas MD Anderson Cancer Center), Michael P. Ryan(The University of Texas MD Anderson Cancer Center), Jing Wang, John N. Weinstein(Boston Children's Hospital), Jiexin Zhang(The University of Texas MD Anderson Cancer Center), Adam Abeshouse, Joshua Armenia(The University of Texas Health Science Center at Houston), Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Galen F. Gao, Benjamin E. Gross, Zachary Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah Phillips, Ed Reznik, Francisco Sánchez-Vega, Chris Sander, Nikolaus Schultz, Robert L. Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang(The University of Texas Health Science Center at Houston), Pavana Anur(The University of Texas MD Anderson Cancer Center), Myron Peto(The University of Texas Health Science Center at Houston), Paul T. Spellman, Christopher C. Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo(Boston Children's Hospital), Richard A. Moore, Andrew J. Mungall(Boston Children's Hospital), Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein(The University of Texas MD Anderson Cancer Center), Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher(The University of Texas MD Anderson Cancer Center), Juliann Shih, Melanie H. Kucherlapati, Raju Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose(The University of Texas MD Anderson Cancer Center), Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly(The University of Texas MD Anderson Cancer Center), Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair(The University of Texas Health Science Center at Houston), Kyle Chang, Kyle R. Covington, Chad J. Creighton(Baylor College of Medicine), Huyen Dinh, HarshaVardhan Doddapaneni(Baylor College of Medicine), Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Hai Hu, Viktoriya Korchina(The University of Texas MD Anderson Cancer Center), Sandra Lee(The University of Texas Health Science Center at Houston), Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan(The University of Texas MD Anderson Cancer Center), Donna Morton, Donna M. Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler(The University of Texas MD Anderson Cancer Center), Xi Liu(The University of Texas MD Anderson Cancer Center), Fengmei Zhao, Julian M. Hess(The University of Texas MD Anderson Cancer Center), Elizabeth L. Appelbaum, Matthew H. Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton(The University of Texas MD Anderson Cancer Center), Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner(Baylor College of Medicine), Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark E. Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall M. Corcoran, Tony Costello, Christopher M. Hovens, André Lopes Carvalho, Ana Carolina de Carvalho, José Humberto Tavares Guerreiro Fregnani, Adhemar Longatto‐Filho, Rui Manuel Reis, Cristovam Scapulatempo‐Neto, Henrique C.S. Silveira, Daniel Onofre Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl(Boston Children's Hospital), Xuan Le, Richard Thorp, Chris Andry(The University of Texas Health Science Center at Houston), Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Shabunin Av, Mikhail Tavobilov, Christopher McPherson, Ronald E. Warnick, Ross S. Berkowitz, Daniel Cramer, Colleen M. Feltmate, Neil S. Horowitz(Baylor College of Medicine), Adam S. Kibel, Michael G. Muto, Chandrajit P. Raut, Andrei Malykh(Boston Children's Hospital), Jill S. Barnholtz‐Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino Maria De Rose, Felice Giuliante, Marc T. Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson(The University of Texas Health Science Center at Houston), Richard Mural, Stella Somiari, Aleš Vícha, Tomáš Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John A. Chabot, Hanina Hibshoosh, Antonia R. Sepulveda, Tao Su, Timothy C. Wang, Olga Potapova, Olga Voronina(The University of Texas MD Anderson Cancer Center), Laurence Desjardins, Odette Mariani, Sergio Roman‐Roman, Xavier Sastre, Marc‐Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell D. Bigner, Eric Lipp, Jeffrey S. Marks, Shannon J. McCall, Roger E. McLendon, Angeles Alvarez Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith A. Delman, Seth Force(The University of Texas MD Anderson Cancer Center), Fadlo R. Khuri, Kelly R. Magliocca, Shishir K. Maithel, Jeffrey J. Olson, Taofeek K. Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir(The University of Texas MD Anderson Cancer Center), Hongzheng Zhang(The University of Texas Health Science Center at Houston), Wil Eijckenboom, Ad Gillis(The University of Texas Health Science Center at Houston), Esther Korpershoek, Leendert H. J. Looijenga(Baylor College of Medicine), Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chen Chu, J. C. Houck, Pawadee Lohavanichbutr(The University of Texas MD Anderson Cancer Center), Arndt Hartmann, Robert Stoehr, Robert Stoehr, Helge Täubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Wung Chung, W. Jeffrey Edenfield, Julie Martin, Éric Baudin, Glenn J. Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven N. Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elı́as Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bùi Đức Phú, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave S.�B. Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia(The University of Texas MD Anderson Cancer Center), Michael J. Birrer, Debra Bell, Mitesh J. Borad(Boston Children's Hospital), Alan H. Bryce, Erik P. Castle, Vishal S. Chandan, John C. Cheville, John A. Copland, Michael B. Farnell, Thomas J. Flotte, Nasra H. Giama(Boston Children's Hospital), Thai H. Ho, Michael L. Kendrick, Jean‐Pierre Kocher(The University of Texas MD Anderson Cancer Center), Karla Kopp(Boston Children's Hospital), Catherine D. Moser, David M. Nagorney, Daniel R. O’Brien, Brian Patrick O’Neill, Tushar Patel(Baylor College of Medicine), Gloria M. Petersen, Florencia G. Que, Michael Rivera, Lewis R. Roberts, Robert C. Smallridge(Boston Children's Hospital), Thomas C. Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang(Boston Children's Hospital), Fadi Brimo, Jaffer A. Ajani(The University of Texas Health Science Center at Houston), Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher J. Logothetis, Funda Meric‐Bernstam, César A. Moran, Lois M. Ramondetta, David C. Rice, Anil K. Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne S. Tsao, Ignacio Wistuba, Candace Carter, Lauren E. Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina V. Long, Graham J. Mann, Michael C. Quinn, Robyn P.M. Saw, Richard A. Scolyer(Boston Children's Hospital), Kerwin F. Shannon, Andrew J. Spillane, Jonathan R. Stretch, Maria Synott, John R. Thompson, James S. Wilmott, Hikmat Al‐Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor E. Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer R. Smith, Howard A. Zaren, Joong‐Won Park, Nguyễn Phi Hùng, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacák, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey I. Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John G. Bartlett, Jay Engel, Sébastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter J. Urba, Nicholas K. Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gian Luca Grazi, Mirella Marino, Roberta Merola, Ronald R. de Krijger, Anne‐Paule Gimenez‐Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kıvanç Birsoy, Gene H. Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski(Baylor College of Medicine), Felicia Williams, Quaid Morris, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran(Boston Children's Hospital), Karl‐Friedrich Becker, Klaus‐Peter Janssen, Julia Slotta‐Huspenina, Mohamed H. Abdel‐Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James C. Lang, Norman L. Lehman, Randy Mandt, Phuong L. Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul E. Wakely, Paul Hansen, Ronald M. Lechan, James Powers, Arthur S. Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima P. Porten, Jens Waldmann, Martin Faßnacht, L. Sylvia, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark A. Nelson, Oliver F. Bathe, Peter R. Carroll, June M. Chan, Philip J. DiSaia, Pat Glenn, Robin Kate Kelley, Charles N. Landen(The University of Texas MD Anderson Cancer Center), Joanna J. Phillips, Michael D. Prados, Jeffry Simko, Karen Smith‐McCune(Boston Children's Hospital), Scott R. VandenBerg, Kevin K. Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis A. Carey, Ian Forgie, Massimo Mannelli, Michael E. Carney(The University of Texas MD Anderson Cancer Center), Brenda Hernandez, Benito Campos(Boston Children's Hospital), Christel Herold‐Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma(Boston Children's Hospital), Mohammed Milhem, Rita Sigmund(Boston Children's Hospital), Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David G. Beer, Thomas J. Giordano, Anne‐Marie Mes‐Masson, Fred Saad, Thèrése Bocklage, Lisa M. Landrum, Robert S. Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan L. Walker, Rosemary E. Zuna, Michaël Feldman, Federico Valdivieso, Rajiv Dhir(Boston Children's Hospital), James D. Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, José Sebastião dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Pretti da Cunha Tirapelli, James W.F. Catto, Kathy Agnew(Baylor College of Medicine), Elizabeth M. Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol R. Bradford, Thomas E. Carey, Andrea Haddad, Jeffey Moyer, Lisa A. Peterson, Mark E. Prince, Laura S. Rozek, Gregory T. Wolf, Rayleen Bowman, Kwun M. Fong, Ian A. Yang, Robert J. Korst, W. Kimryn Rathmell(The University of Texas MD Anderson Cancer Center), J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John F. DiPersio, Bettina F. Drake, Ramaswamy Govindan, Sharon E. Heath, Timothy J. Ley, Brian A. Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, Fernando D. Camargo(Harvard Stem Cell Institute), Han Liang(The University of Texas MD Anderson Cancer Center)
Cited by 512Open Access
Abstract
Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional "omic" data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era.