Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma.

Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR, Lichtenberg TM, Murray BA, Ghayee HK, Else T, Ling S, Jefferys SR, de Cubas AA, Wenz B, Korpershoek E, Amelio AL, Makowski L, Rathmell WK, Gimenez-Roqueplo AP, Giordano TJ, Asa SL, Tischler AS, Cancer Genome Atlas Research Network, Pacak K, Nathanson KL, Wilkerson MD
Cancer Cell. 2017 31 (2): 181-193

PMID: 28162975 · PMCID: PMC5643159 · DOI:10.1016/j.ccell.2017.01.001

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.

Copyright © 2017 Elsevier Inc. All rights reserved.

MeSH Terms (17)

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

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