Comprehensive molecular characterization of the hippo signaling pathway in cancer

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.

Metadata

Authors/Creators:	Wang, Y Xu, X Maglic, D Dill, MT Mojumdar, K Ng, PK-S Jeong, KJ Tsang, YH Moreno, D Bhavana, VH Peng, X Ge, Z Chen, H Li, J Chen, Z Zhang, H Han, L Du, D Creighton, CJ Mills, GB Camargo, F Liang, H Caesar-Johnson, SJ Demchok, JA Felau, I Kasapi, M Ferguson, ML Hutter, CM Sofia, HJ Tarnuzzer, R Wang, Z Yang, L Zenklusen, JC Zhang, JJ Chudamani, S Liu, J Lolla, L Naresh, R Pihl, T Sun, Q Wan, Y Wu, Y Cho, J DeFreitas, T Frazer, S Gehlenborg, N Getz, G Heiman, DI Kim, J Lawrence, MS Lin, P Meier, S Noble, MS Saksena, G Voet, D Zhang, H Bernard, B Chambwe, N Dhankani, V Knijnenburg, T Kramer, R Leinonen, K Liu, Y Miller, M Reynolds, S Shmulevich, I Thorsson, V Zhang, W Akbani, R Broom, BM Hegde, AM Ju, Z Kanchi, RS Korkut, A Li, J Liang, H Ling, S Liu, W Lu, Y Mills, GB Ng, K-S Rao, A Ryan, M Wang, J Weinstein, JN Zhang, J Abeshouse, A Armenia, J Chakravarty, D Chatila, WK de Bruijn, I Gao, J Gross, BE Heins, ZJ Kundra, R La, K Ladanyi, M Luna, A Nissan, MG Ochoa, A Phillips, SM Reznik, E Sanchez-Vega, F Sander, C Schultz, N Sheridan, R Sumer, SO Sun, Y Taylor, BS Wang, J Zhang, H Anur, P Peto, M Spellman, P Benz, C Stuart, JM Wong, CK Yau, C Hayes, DN Parker, JS Wilkerson, MD Ally, A Balasundaram, M Bowlby, R Brooks, D Carlsen, R Chuah, E Dhalla, N Holt, R Jones, SJM Kasaian, K Lee, D Ma, Y Marra, MA Mayo, M Moore, RA Mungall, AJ Mungall, K Robertson, AG Sadeghi, S Schein, JE Sipahimalani, P Tam, A Thiessen, N Tse, K Wong, T Berger, AC Beroukhim, R Cherniack, AD Cibulskis, C Gabriel, SB Gao, GF Ha, G Meyerson, M Schumacher, SE Shih, J Kucherlapati, MH Kucherlapati, RS Baylin, S Cope, L Danilova, L Bootwalla, MS Lai, PH Maglinte, DT Van Den Berg, DJ Weisenberger, DJ Auman, JT Balu, S Bodenheimer, T Fan, C Hoadley, KA Hoyle, AP Jefferys, SR Jones, CD Meng, S Mieczkowski, PA Mose, LE Perou, AH Perou, CM Roach, J Shi, Y Simons, JV Skelly, T Soloway, MG Tan, D Veluvolu, U Fan, H Hinoue, T Laird, PW Shen, H Zhou, W Bellair, M Chang, K Covington, K Creighton, CJ Dinh, H Doddapaneni, H Donehower, LA Drummond, J Gibbs, RA Glenn, R Hale, W Han, Y Hu, J Korchina, V Lee, S Lewis, L Li, W Liu, X Morgan, M Morton, D Muzny, D Santibanez, J Sheth, M Shinbrot, E Wang, L Wang, M Wheeler, DA Xi, L Zhao, F Hess, J Appelbaum, EL Bailey, M Cordes, MG Ding, L Fronick, CC Fulton, LA Fulton, RS Kandoth, C Mardis, ER McLellan, MD Miller, CA Schmidt, HK Wilson, RK Crain, D Curley, E Gardner, J Lau, K Mallery, D Morris, S Paulauskis, J Penny, R Shelton, C Shelton, T Sherman, M Thompson, E Yena, P Bowen, J Gastier-Foster, JM Gerken, M Leraas, KM Lichtenberg, TM Ramirez, NC Wise, L Zmuda, E Corcoran, N Costello, T Hovens, C Carvalho, AL de Carvalho, AC Fregnani, JH Longatto-Filho, A Reis, RM Scapulatempo-Neto, C Silveira, HCS Vidal, DO Burnette, A Eschbacher, J Hermes, B Noss, A Singh, R Anderson, ML Castro, PD Ittmann, M Huntsman, D Kohl, B Le, X Thorp, R Andry, C Duffy, ER Lyadov, V Paklina, O Setdikova, G Shabunin, A Tavobilov, M McPherson, C Warnick, R Berkowitz, R Cramer, D Feltmate, C Horowitz, N Kibel, A Muto, M Raut, CP Malykh, A Barnholtz-Sloan, JS Barrett, W Devine, K Fulop, J Ostrom, QT Shimmel, K Wolinsky, Y Sloan, AE De Rose, A Giuliante, F Goodman, M Karlan, BY Hagedorn, CH Eckman, J Harr, J Myers, J Tucker, K Zach, LA Deyarmin, B Hu, H Kvecher, L Larson, C Mural, RJ Somiari, S Vicha, A Zelinka, T Bennett, J Iacocca, M Rabeno, B Swanson, P Latour, M Lacombe, L Têtu, B Bergeron, A McGraw, M Staugaitis, SM Chabot, J Hibshoosh, H Sepulveda, A Su, T Wang, T Potapova, O Voronina, O Desjardins, L Mariani, O Roman-Roman, S Sastre, X Stern, M-H Cheng, F Signoretti, S Berchuck, A Bigner, D Lipp, E Marks, J McCall, S McLendon, R Secord, A Sharp, A Behera, M Brat, DJ Chen, A Delman, K Force, S Khuri, F Magliocca, K Maithel, S Olson, JJ Owonikoko, T Pickens, A Ramalingam, S Shin, DM Sica, G Van Meir, EG Zhang, H Eijckenboom, W Gillis, A Korpershoek, E Looijenga, L Oosterhuis, W Stoop, H van Kessel, KE Zwarthoff, EC Calatozzolo, C Cuppini, L Cuzzubbo, S DiMeco, F Finocchiaro, G Mattei, L Perin, A Pollo, B Chen, C Houck, J Lohavanichbutr, P Hartmann, A Stoehr, C Stoehr, R Taubert, H Wach, S Wullich, B Kycler, W Murawa, D Wiznerowicz, M Chung, K Edenfield, WJ Martin, J Baudin, E Bubley, G Bueno, R De Rienzo, A Richards, WG Kalkanis, S Mikkelsen, T Noushmehr, H Scarpace, L Girard, N Aymerich, M Campo, E Giné, E Guillermo, AL Van Bang, N Hanh, PT Phu, BD Tang, Y Colman, H Evason, K Dottino, PR Martignetti, JA Gabra, H Juhl, H Akeredolu, T Stepa, S Hoon, D Ahn, K Kang, KJ Beuschlein, F Breggia, A Birrer, M Bell, D Borad, M Bryce, AH Castle, E Chandan, V Cheville, J Copland, JA Farnell, M Flotte, T Giama, N Ho, T Kendrick, M Kocher, J-P Kopp, K Moser, C Nagorney, D O’Brien, D O’Neill, BP Patel, T Petersen, G Que, F Rivera, M Roberts, L Smallridge, R Smyrk, T Stanton, M Thompson, RH Torbenson, M Yang, JD Zhang, L Brimo, F Ajani, JA Gonzalez, AMA Behrens, C Bondaruk, J Broaddus, R Czerniak, B Esmaeli, B Fujimoto, J Gershenwald, J Guo, C Lazar, AJ Logothetis, C Meric-Bernstam, F Moran, C Ramondetta, L Rice, D Sood, A Tamboli, P Thompson, T Troncoso, P Tsao, A Wistuba, I Carter, C Haydu, L Hersey, P Jakrot, V Kakavand, H Kefford, R Lee, K Long, G Mann, G Quinn, M Saw, R Scolyer, R Shannon, K Spillane, A Stretch, J Synott, M Thompson, J Wilmott, J Al-Ahmadie, H Chan, TA Ghossein, R Gopalan, A Levine, DA Reuter, V Singer, S Singh, B Tien, NV Broudy, T Mirsaidi, C Nair, P Drwiega, P Miller, J Smith, J Zaren, H Park, J-W Hung, NP Kebebew, E Linehan, WM Metwalli, AR Pacak, K Pinto, PA Schiffman, M Schmidt, LS Vocke, CD Wentzensen, N Worrell, R Yang, H Moncrieff, M Goparaju, C Melamed, J Pass, H Botnariuc, N Caraman, I Cernat, M Chemencedji, I Clipca, A Doruc, S Gorincioi, G Mura, S Pirtac, M Stancul, I Tcaciuc, D Albert, M Alexopoulou, I Arnaout, A Bartlett, J Engel, J Gilbert, S Parfitt, J Sekhon, H Thomas, G Rassl, DM Rintoul, RC Bifulco, C Tamakawa, R Urba, W Hayward, N Timmers, H Antenucci, A Facciolo, F Grazi, G Marino, M Merola, R de Krijger, R Gimenez-Roqueplo, A-P Piché, A Chevalier, S McKercher, G Birsoy, K Barnett, G Brewer, C Farver, C Naska, T Pennell, NA Raymond, D Schilero, C Smolenski, K Williams, F Morrison, C Borgia, JA Liptay, MJ Pool, M Seder, CW Junker, K Omberg, L Dinkin, M Manikhas, G Alvaro, D Bragazzi, MC Cardinale, V Carpino, G Gaudio, E Chesla, D Cottingham, S Dubina, M Moiseenko, F Dhanasekaran, R Becker, K-F Janssen, K-P Slotta-Huspenina, J Abdel-Rahman, MH Aziz, D Bell, S Cebulla, CM Davis, A Duell, R Elder, JB Hilty, J Kumar, B Lang, J Lehman, NL Mandt, R Nguyen, P Pilarski, R Rai, K Schoenfield, L Senecal, K Wakely, P Hansen, P Lechan, R Powers, J Tischler, A Grizzle, WE Sexton, KC Kastl, A Henderson, J Porten, S Waldmann, J Fassnacht, M Asa, SL Schadendorf, D Couce, M Graefen, M Huland, H Sauter, G Schlomm, T Simon, R Tennstedt, P Olabode, O Nelson, M Bathe, O Carroll, PR Chan, JM Disaia, P Glenn, P Kelley, RK Landen, CN Phillips, J Prados, M Simko, J Smith-McCune, K VandenBerg, S Roggin, K Fehrenbach, A Kendler, A Sifri, S Steele, R Jimeno, A Carey, F Forgie, I Mannelli, M Carney, M Hernandez, B Campos, B Herold-Mende, C Jungk, C Unterberg, A von Deimling, A Bossler, A Galbraith, J Jacobus, L Knudson, M Knutson, T Ma, D Milhem, M Sigmund, R Godwin, AK Madan, R Rosenthal, HG Adebamowo, C Adebamowo, SN Boussioutas, A Beer, D Giordano, T Mes-Masson, A-M Saad, F Bocklage, T Landrum, L Mannel, R Moore, K Moxley, K Postier, R Walker, J Zuna, R Feldman, M Valdivieso, F Dhir, R Luketich, J Pinero, EMM Quintero-Aguilo, M Carlotti, CG Dos Santos, JS Kemp, R Sankarankuty, A Tirapelli, D Catto, J https://orcid.org/0000-0003-2787-8828 Agnew, K Swisher, E Creaney, J Robinson, B Shelley, CS Godwin, EM Kendall, S Shipman, C Bradford, C Carey, T Haddad, A Moyer, J Peterson, L Prince, M Rozek, L Wolf, G Bowman, R Fong, KM Yang, I Korst, R Rathmell, WK Fantacone-Campbell, JL Hooke, JA Kovatich, AJ Shriver, CD DiPersio, J Drake, B Govindan, R Heath, S Ley, T Van Tine, B Westervelt, P Rubin, MA Lee, JI Aredes, ND Mariamidze, A
Copyright, Publisher and Additional Information:	© 2018 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) .
Keywords:	TCGA; Pan-cancer analysis; Driver mutation; miRNA regulation; Pathway activity; Tumor subtype; YAP; TAZ; Prognostic power
Dates:	Accepted: 28 September 2018 Published (online): 30 October 2018 Published: 30 October 2018
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	23 Oct 2019 12:00
Last Modified:	23 Oct 2019 12:00
Status:	Published
Publisher:	Elsevier
Refereed:	Yes
Identification Number:	https://doi.org/10.1016/j.celrep.2018.10.001
Related URLs:	PubMed URL

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Comprehensive molecular characterization of the hippo signaling pathway in cancer

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