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 Giordano; Sylvia L Asa; Arthur S Tischler; Cancer Genome Atlas Research Network; Karel Pacak; Katherine L Nathanson; Matthew D Wilkerson

doi:10.1016/j.ccell.2017.01.001

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Cancer Cell. 2017 Feb 13;31(2):181-193. doi: 10.1016/j.ccell.2017.01.001. Epub 2017 Feb 2.

Authors

Lauren Fishbein¹, Ignaty Leshchiner², Vonn Walter³, Ludmila Danilova⁴, A Gordon Robertson⁵, Amy R Johnson⁶, Tara M Lichtenberg⁷, Bradley A Murray², Hans K Ghayee⁸, Tobias Else⁹, Shiyun Ling¹⁰, Stuart R Jefferys³, Aguirre A de Cubas¹¹, Brandon Wenz¹², Esther Korpershoek¹³, Antonio L Amelio³, Liza Makowski¹⁴, W Kimryn Rathmell¹¹, Anne-Paule Gimenez-Roqueplo¹⁵, Thomas J Giordano¹⁶, Sylvia L Asa¹⁷, Arthur S Tischler¹⁸; Cancer Genome Atlas Research Network; Karel Pacak¹⁹, Katherine L Nathanson²⁰, Matthew D Wilkerson²¹

Collaborators

Cancer Genome Atlas Research Network:
Rehan Akbani, Adrian Ally, Laurence Amar, Antonio L Amelio, Harindra Arachchi, Sylvia L Asa, 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, Ludmila Danilova, Aguirre A de Cubas, Ronald R de Krijger, John A Demchok, Timo Deutschbein, Noreen Dhalla, David Dimmock, Winand N M Dinjens, Tobias Else, Charis Eng, Jennifer Eschbacher, Martin Fassnacht, Ina Felau, Michael Feldman, Martin L Ferguson, Ian Fiddes, Lauren Fishbein, Scott Frazer, Stacey B Gabriel, Johanna Gardner, Julie M Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, Jennifer Geurts, Hans K Ghayee, Anne-Paule Gimenez-Roqueplo, Thomas J Giordano, 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, Stuart R Jefferys, Amy R Johnson, Steven J M Jones, Corbin D Jones, Katayoon Kasaian, Electron Kebebew, Jaegil Kim, Patrick Kimes, Theo Knijnenburg, Esther Korpershoek, Eric Lander, Michael S Lawrence, Ronald Lechan, Darlene Lee, Kristen M Leraas, Antonio Lerario, Ignaty Leshchiner, Tara M Lichtenberg, Pei Lin, Shiyun Ling, Jia Liu, Virginia A LiVolsi, Laxmi Lolla, Yair Lotan, Yiling Lu, Yussanne Ma, Nicole Maison, Liza Makowski, 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, Bradley A Murray, 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, W Kimryn Rathmell, Anna Riester, Jeffrey Roach, A Gordon Robertson, 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, Arthur S Tischler, Kane Tse, Vlado Uzunangelov, Anouk van Berkel, Umadevi Veluvolu, Ales Vicha, Doug Voet, Jens Waldmann, Vonn Walter, Yunhu Wan, Zhining Wang, Tracy S Wang, Joellen Weaver, John N Weinstein, Dirk Weismann, Brandon Wenz, 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

Affiliations

¹ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
² The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
³ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA.
⁵ Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
⁶ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
⁸ Division of Endocrinology & Metabolism, Department of Medicine, University of Florida College of Medicine & Malcom Randall VA Medical Center, Gainesville, FL 32608, USA.
⁹ Division of Metabolism, Endocrinology, & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
¹⁰ University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹² Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
¹³ Department of Pathology, Erasmus MC University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
¹⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁵ INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France.
¹⁶ Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
¹⁷ Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 2C4, Canada.
¹⁸ Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA 02111, USA.
¹⁹ Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA. Electronic address: karel@mail.nih.gov.
²⁰ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: knathans@exchange.upenn.edu.
²¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: mdwilkerson@outlook.com.

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.

Keywords: CSDE1; MAML3; TCGA; expression subtypes; genomics; metastasis; molecular profiling; paraganglioma; pheochromocytoma; sequencing.

MeSH terms

Adult
Aged
Aged, 80 and over
DNA-Binding Proteins / genetics
Female
Gene Fusion
Humans
Male
Middle Aged
Mutation
Nuclear Proteins / genetics
Paraganglioma / etiology
Paraganglioma / genetics*
Pheochromocytoma / etiology
Pheochromocytoma / genetics*
Pol1 Transcription Initiation Complex Proteins / genetics
Proto-Oncogene Proteins c-ret / genetics
RNA-Binding Proteins / genetics
Trans-Activators
Transcription Factors / genetics

Substances

CSDE1 protein, human
DNA-Binding Proteins
MAML3 protein, human
Nuclear Proteins
Pol1 Transcription Initiation Complex Proteins
RNA-Binding Proteins
Trans-Activators
Transcription Factors
transcription factor UBF
Proto-Oncogene Proteins c-ret
RET protein, human

Abstract

MeSH terms

Substances

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