Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

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.

Citation

L Fishbein, I Leshchiner, V Walter, L Danilova, AG Robertson, AR Johnson, TM Lichtenberg, BA Murray, HK Ghayee, T Else, S Ling, SR Jefferys, AA De Cubas, B Wenz, E Korpershoek, AL Amelio, L Makowski, WK Rathmell, AP Gimenez-Roqueplo, TJ Giordano, SL Asa, AS Tischler, The Cancer Genome Atlast Research Network (incl. N Gehlenborg), K Pacak, KL Nathanson, MD Wilkerson. “Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma”, Cancer Cell 31(2):181-193 (2017). doi:10.1016/j.ccell.2017.01.001