Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma
Martin Faßnacht, Manaswi Gupta, Anouk van Berkel(University of North Carolina at Chapel Hill), Jessica Marquard, Tobias Else, Ian T. Fiddes, Ilya Shmulevich, Ignaty Leshchiner, Özgür Mete, Heidi J. Sofia, Julie M. Gastier-Foster, Antonio L. Amelio(University of North Carolina at Chapel Hill), Richard J. Auchus(University of North Carolina at Chapel Hill), Daniel Crain, Jay Bowen, Shiyun Ling(University of North Carolina at Chapel Hill), Joel S. Parker(University of North Carolina at Chapel Hill), Sofie R. Salama(University of North Carolina at Chapel Hill), Tom Bodenheimer, Katherine Tarvin, David Haussler, Todd Pihl, Silviu Sbiera, Rehan Akbani, Massimo Mannelli, Liza Makowski(University of North Carolina at Chapel Hill), Virginia A. LiVolsi, Kane Tse, Winand N.M. Dinjens, Amy R. Johnson(University of North Carolina at Chapel Hill), David Haan, Christopher X. Wong, Stefanie Hahner, Eric S. Lander, Anna Riester, Evan D. Paul, Nicole Maison, Sam Ng, Electron Kebebew, Antônio Marcondes Lerário, Noreen Dhalla, Wang, Zhining, Charles M. Perou, Martin L. Ferguson, J. Todd Auman, Vonn Walter(University of North Carolina at Chapel Hill), Eric Chuah, Kristen M. Leraas, Sylvia L. Asa, Robert Baertsch, Katherine L. Nathanson, Laurence Amar, Troy Shelton, John A. Demchok, Uzunangelov, Vlado, Corbin D. Jones, Yan Shi, Jacqueline E. Schein, Joshua M. Stuart, Esther Korpershoek, Marco A. Marra, Jennifer Rabaglia, Tina Wong, Doug Voet, Juliann Shih, Steven E. Schumacher, W. Kimryn Rathmell(University of North Carolina at Chapel Hill), Wei Zhang, Constanze Hantel, Andrew D. Cherniack, Aleš Vícha, Gad Getz, Mark Gerken, Timo Deutschbein, Kasaian, Katayoon, Charis Eng, Brandon M. Wenz, Jens Waldmann, Suzie Carter, Bradley A. Murray, Joellen Weaver, Alan P. Hoyle, Teresa Swatloski, Rebecca Carlsen, Rashi Naresh, Nilsa C. Ramirez, Scott Morris, Amy H. Perou, Leslie Cope, Leigh B. Thorne, Olena Morozova, Matthew Thomas, Jeffrey Roach, Janae V. Simons, Charlie Sun, Yiling Lu, Amie Radenbaugh, Thomas Bauer, Ying Ni, Michael S. Noble, Éric Baudin, Jingchun Zhu, Detlef K. Bartsch, Jiashan Zhang, Saianand Balu, Thomas J. Giordano, Ronald M. Lechan, Shaowu Meng, Felix Beuschlein, Tara Skelly, Carolyn M. Hutter, Hans K. Ghayee, Scott Frazer, Angela Tam, Lisa Wise, Robert A. Holt, Ludmila Danilova, Bryan Hunt, Gordon B. Mills, Patrick K. Kimes, Candace Shelton, Erik Zmuda, Stacey Gabriel, Yussanne Ma, Sudha Chudamani, D. Neil Hayes, Miruna Balasundaram, Jia Liu, Tracy Wang, Mei Huang, Matthew Meyerson, Richard A. Moore, David I. Heiman, Reanne Bowlby, Robert Penny, Yunhu Wan, Michael S. Lawrence, Franck Zinzindohoué, David Mallery, Karel Pacák, Harindra Arachchi, Denise Brooks, Dirk Weismann, Andrew J. Mungall, Ye Wu, Laxmi Lolla, Donghui Tan, Maria J. Merino, Christopher C. Benz, Erin Curley, Jean C. Zenklusen, Jaegil Kim, Aguirre A. de Cubas(University of North Carolina at Chapel Hill), Michaël Feldman, Arthur S. Tischler, Theo Knijnenburg, Lauren Fishbein, Ina Felau, Artem Sokolov, Johanna Gardner, Yulia Newton, A. Gordon Robertson, Tomáš Zelinka, Michael Mayo, Darlene Lee, John N. Weinstein, Mary J. Goldman, Ronald R. de Krijger, Carrie Sougnez, Nils Gehlenborg, Kiley Graim, James F. Powers, Clarissa A. Cassol, Lynda Chin, Tara M. Lichtenberg, Roy Tarnuzzer, Yair Lotan, David Dimmock, Henri Timmers, Jennifer Eschbacher, Jefferys, Stuart R.(University of North Carolina at Chapel Hill), George E. Sandusky, Lisle E. Mose, Nina Thiessen, Anne‐Paule Gimenez‐Roqueplo, Gordon Saksena, Pei Lin, Juok Cho, Fiemu E. Nwariaku, Adrian Ally, Katherine A. Hoadley, Sara Sadeghi, Liming Yang, Arjun A. Rao, Tchao Méatchi(University of North Carolina at Chapel Hill), Charles Saller, Umadevi Veluvolu, Piotr A. Mieczkowski, Payal Sipahimalani, Matthew D. Wilkerson(University of North Carolina at Chapel Hill), Allison Beaver, Steven J.M. Jones, Matthew G. Soloway, Rameen Beroukhim, Jennifer L. Geurts, Margi Sheth, Lori Boice
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Abstract
SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.
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