Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Publication date: Available online 2 February 2017
Source:Cancer Cell
Author(s): 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, Karel Pacak, Katherine L. Nathanson, Matthew D. Wilkerson
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.

Graphical abstract

Teaser

Fishbein et al. show that neuroendocrine tumors, pheochromocytomas and paragangliomas, have a low genome alteration rate but diverse driver alterations, which coalesce into four molecular subtypes. The Wnt-altered subtype, driven by MAML3 fusions and CSDE1 somatic mutations, correlates with poor clinical outcome.


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