Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Lauren Fishbein, Ignaty Leshchiner, Vonn Walter, Ludmila Danilova, A. Gordon Robertson, Amy R. Johnson, Tara M. Lichtenberg, Bradley A. Murray, Hans K. Ghayee, Tobias Else, Shiyun Ling, Stuart R. Jefferys, Aguirre A. de Cubas, Brandon Wenz, Esther Korpershoek, Antonio L. Amelio, Liza Makowski, W. Kimryn Rathmell, Anne Paule Gimenez-Roqueplo, Thomas J. GiordanoSylvia L. Asa, Arthur S. Tischler, Rehan Akbani, Adrian Ally, Laurence Amar, Harindra Arachchi, Richard J. Auchus, J. Todd Auman, Robert Baertsch, Miruna Balasundaram, Saianand Balu, Detlef K. Bartsch, Eric Baudin, Thomas Bauer, Allison Beaver, Christopher Benz, Rameen Beroukhim, Felix Beuschlein, Tom Bodenheimer, Lori Boice, Jay Bowen, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Suzie Carter, Clarissa A. Cassol, Andrew D. Cherniack, Lynda Chin, Juok Cho, Eric Chuah, Sudha Chudamani, Leslie Cope, Daniel Crain, Erin Curley, Ronald R. de Krijger, John A. Demchok, Timo Deutschbein, Noreen Dhalla, David Dimmock, Winand N.M. Dinjens, Charis Eng, Jennifer Eschbacher, Martin Fassnacht, Ina Felau, Michael Feldman, Martin L. Ferguson, Ian Fiddes, Scott Frazer, Stacey B. Gabriel, Johanna Gardner, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, Jennifer Geurts, Mary Goldman, Kiley Graim, Manaswi Gupta, David Haan, Stefanie Hahner, Constanze Hantel, David Haussler, D. Neil Hayes, David I. Heiman, Katherine A. Hoadley, Robert A. Holt, Alan P. Hoyle, Mei Huang, Bryan Hunt, Carolyn M. Hutter, Steven J.M. Jones, Corbin D. Jones, Katayoon Kasaian, Electron Kebebew, Jaegil Kim, Patrick Kimes, Theo Knijnenburg, Eric Lander, Michael S. Lawrence, Ronald Lechan, Darlene Lee, Kristen M. Leraas, Antonio Lerario, Pei Lin, Jia Liu, Virginia A. LiVolsi, Laxmi Lolla, Yair Lotan, Yiling Lu, Yussanne Ma, Nicole Maison, David Mallery, Massimo Mannelli, Jessica Marquard, Marco A. Marra, Thomas Matthew, Michael Mayo, Tchao Méatchi, Shaowu Meng, Maria J. Merino, Ozgur Mete, Matthew Meyerson, Piotr A. Mieczkowski, Gordon B. Mills, Richard A. Moore, Olena Morozova, Scott Morris, Lisle E. Mose, Andrew J. Mungall, Rashi Naresh, Katherine L. Nathanson, Yulia Newton, Sam Ng, Ying Ni, Michael S. Noble, Fiemu Nwariaku, Karel Pacak, Joel S. Parker, Evan Paul, Robert Penny, Charles M. Perou, Amy H. Perou, Todd Pihl, James Powers, Jennifer Rabaglia, Amie Radenbaugh, Nilsa C. Ramirez, Arjun Rao, Anna Riester, Jeffrey Roach, Sara Sadeghi, Gordon Saksena, Sofie Salama, Charles Saller, George Sandusky, Silviu Sbiera, Jacqueline E. Schein, Steven E. Schumacher, Candace Shelton, Troy Shelton, Margi Sheth, Yan Shi, Juliann Shih, Ilya Shmulevich, Janae V. Simons, Payal Sipahimalani, Tara Skelly, Heidi J. Sofia, Artem Sokolov, Matthew G. Soloway, Carrie Sougnez, Josh Stuart, Charlie Sun, Teresa Swatloski, Angela Tam, Donghui Tan, Roy Tarnuzzer, Katherine Tarvin, Nina Thiessen, Leigh B. Thorne, Henri J. Timmers, Kane Tse, Vlado Uzunangelov, Anouk van Berkel, Umadevi Veluvolu, Ales Vicha, Doug Voet, Jens Waldmann, Yunhu Wan, Zhining Wang, Tracy S. Wang, Joellen Weaver, John N. Weinstein, Dirk Weismann, Matthew D. Wilkerson, Lisa Wise, Tina Wong, Christopher Wong, Ye Wu, Liming Yang, Tomas Zelinka, Jean C. Zenklusen, Jiashan (Julia) Zhang, Wei Zhang, Jingchun Zhu, Franck Zinzindohoué, Erik Zmuda

    Research output: Contribution to journalArticle

    169 Scopus citations

    Abstract

    We 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.

    Original languageEnglish (US)
    Pages (from-to)181-193
    Number of pages13
    JournalCancer Cell
    Volume31
    Issue number2
    DOIs
    StatePublished - Feb 13 2017

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    Keywords

    • CSDE1
    • MAML3
    • TCGA
    • expression subtypes
    • genomics
    • metastasis
    • molecular profiling
    • paraganglioma
    • pheochromocytoma
    • sequencing

    ASJC Scopus subject areas

    • Oncology
    • Cell Biology
    • Cancer Research

    Cite this

    Fishbein, L., Leshchiner, I., Walter, V., Danilova, L., Robertson, A. G., Johnson, A. R., Lichtenberg, T. M., Murray, B. A., Ghayee, H. K., Else, T., Ling, S., Jefferys, S. R., de Cubas, A. A., Wenz, B., Korpershoek, E., Amelio, A. L., Makowski, L., Rathmell, W. K., Gimenez-Roqueplo, A. P., ... Zmuda, E. (2017). Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell, 31(2), 181-193. https://doi.org/10.1016/j.ccell.2017.01.001