Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma
A partir de 173 échantillons tumoraux prélevés sur des patients atteints d'une tumeur neuroendocrine rare (paragangliome/phéochromocytome), cette étude identifie un ensemble d'anomalies moléculaires (mutations constitutionnelles ou somatiques, fusions de gènes) permettant de définir quatre sous-groupes de la maladie
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. Highlights •Comprehensive molecular profiling of 173 pheochromocytoma and paraganglioma tumors •Single drivers in tumors by germline mutation, somatic mutation, or fusion gene •MAML3 fusion gene and CSDE1 somatic mutation define a Wnt-altered subtype •Prognostic markers of metastatic disease include the MAML3 fusion gene