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. 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.

Additional Metadata
Keywords CSDE1, Expression subtypes, Genomics, MAML3, Metastasis, Molecular profiling, Paraganglioma, Pheochromocytoma, Sequencing, TCGA
Persistent URL dx.doi.org/10.1016/j.ccell.2017.01.001, hdl.handle.net/1765/95832
Journal Cancer Cell
Fishbein, L. (Lauren), Leshchiner, I. (Ignaty), Walter, V. (Vonn), Danilova, L. (Ludmila), Robertson, A.G. (A. Gordon), Johnson, A.R. (Amy R.), … Wilkerson, M.D. (Matthew D.). (2016). Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell. doi:10.1016/j.ccell.2017.01.001