Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma
Publication date
2017-02-13
Authors
Fishbein, Lauren
Leshchiner, Ignaty
Walter, Vonn
Danilova, Ludmila
Robertson, A. Gordon
Johnson, Amy R.
Lichtenberg, Tara M.
Murray, Bradley A.
Ghayee, Hans K.
Else, Tobias
Editors
Advisors
Supervisors
Document Type
Article
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taverne
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, expression subtypes, genomics, MAML3, metastasis, molecular profiling, paraganglioma, pheochromocytoma, sequencing, TCGA, Taverne, Oncology, Cell Biology, Cancer Research, Journal Article
Citation
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, Giordano, T J, Asa, S L, Tischler, A S, Akbani, R, Ally, A, Amar, L, Amelio, A L, Arachchi, H, Asa, S L, Auchus, R J, Auman, J T, Baertsch, R, Balasundaram, M, Balu, S, Bartsch, D K, Baudin, E, Bauer, T, Beaver, A, Benz, C, Beroukhim, R, Beuschlein, F, Bodenheimer, T, Boice, L, Bowen, J, Bowlby, R, Brooks, D, Carlsen, R, Carter, S, Cassol, C A, Cherniack, A D, Chin, L, Cho, J, Chuah, E, Chudamani, S, Cope, L, Crain, D, Curley, E, Danilova, L, de Cubas, A A, de Krijger, R R, Demchok, J A, Deutschbein, T, Dhalla, N, Dimmock, D, Dinjens, W N M, Else, T, Eng, C, Eschbacher, J, Fassnacht, M, Felau, I, Feldman, M, Ferguson, M L, Fiddes, I, Fishbein, L, Frazer, S, Gabriel, S B, Gardner, J, Gastier-Foster, J M, Gehlenborg, N, Gerken, M, Getz, G, Geurts, J, Ghayee, H K, Gimenez-Roqueplo, A P, Giordano, T J, Goldman, M, Graim, K, Gupta, M, Haan, D, Hahner, S, Hantel, C, Haussler, D, Hayes, D N, Heiman, D I, Hoadley, K A, Holt, R A, Hoyle, A P, Huang, M, Hunt, B, Hutter, C M, Jefferys, S R, Johnson, A R, Jones, S J M, Jones, C D, Kasaian, K, Kebebew, E, Kim, J, Kimes, P, Knijnenburg, T, Korpershoek, E, Lander, E, Lawrence, M S, Lechan, R, Lee, D, Leraas, K M, Lerario, A, Leshchiner, I, Lichtenberg, T M, Lin, P, Ling, S, Liu, J, LiVolsi, V A, Lolla, L, Lotan, Y, Lu, Y, Ma, Y, Maison, N, Makowski, L, Mallery, D, Mannelli, M, Marquard, J, Marra, M A, Matthew, T, Mayo, M, Méatchi, T, Meng, S, Merino, M J, Mete, O, Meyerson, M, Mieczkowski, P A, Mills, G B, Moore, R A, Morozova, O, Morris, S, Mose, L E, Mungall, A J, Murray, B A, Naresh, R, Nathanson, K L, Newton, Y, Ng, S, Ni, Y, Noble, M S, Nwariaku, F, Pacak, K, Parker, J S, Paul, E, Penny, R, Perou, C M, Perou, A H, Pihl, T, Powers, J, Rabaglia, J, Radenbaugh, A, Ramirez, N C, Rao, A, Rathmell, W K, Riester, A, Roach, J, Robertson, A G, Sadeghi, S, Saksena, G, Salama, S, Saller, C, Sandusky, G, Sbiera, S, Schein, J E, Schumacher, S E, Shelton, C, Shelton, T, Sheth, M, Shi, Y, Shih, J, Shmulevich, I, Simons, J V, Sipahimalani, P, Skelly, T, Sofia, H J, Sokolov, A, Soloway, M G, Sougnez, C, Stuart, J, Sun, C, Swatloski, T, Tam, A, Tan, D, Tarnuzzer, R, Tarvin, K, Thiessen, N, Thorne, L B, Timmers, H J, Tischler, A S, Tse, K, Uzunangelov, V, van Berkel, A, Veluvolu, U, Vicha, A, Voet, D, Waldmann, J, Walter, V, Wan, Y, Wang, Z, Wang, T S, Weaver, J, Weinstein, J N, Weismann, D, Wenz, B, Wilkerson, M D, Wise, L, Wong, T, Wong, C, Wu, Y, Yang, L, Zelinka, T, Zenklusen, J C, Zhang, J, Zhang, W, Zhu, J, Zinzindohoué, F, Zmuda, E, Pacak, K, Nathanson, K L & Wilkerson, M D 2017, 'Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma', Cancer Cell, vol. 31, no. 2, pp. 181-193. https://doi.org/10.1016/j.ccell.2017.01.001