Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Cancer Cell. 2017 Feb 13;31(2):181-193. doi: 10.1016/j.ccell.2017.01.001. Epub 2017 Feb 2.


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.

Keywords: CSDE1; MAML3; TCGA; expression subtypes; genomics; metastasis; molecular profiling; paraganglioma; pheochromocytoma; sequencing.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • DNA-Binding Proteins / genetics
  • Female
  • Gene Fusion
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Nuclear Proteins / genetics
  • Paraganglioma / etiology
  • Paraganglioma / genetics*
  • Pheochromocytoma / etiology
  • Pheochromocytoma / genetics*
  • Pol1 Transcription Initiation Complex Proteins / genetics
  • Proto-Oncogene Proteins c-ret / genetics
  • RNA-Binding Proteins / genetics
  • Trans-Activators
  • Transcription Factors / genetics


  • CSDE1 protein, human
  • DNA-Binding Proteins
  • MAML3 protein, human
  • Nuclear Proteins
  • Pol1 Transcription Initiation Complex Proteins
  • RNA-Binding Proteins
  • Trans-Activators
  • Transcription Factors
  • transcription factor UBF
  • Proto-Oncogene Proteins c-ret
  • RET protein, human