Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma
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.
|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|
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