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.
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Lauren
L
Fishbein
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
Ignaty
I
Leshchiner
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Vonn
V
Walter
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA.
Ludmila
L
Danilova
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
A Gordon
AG
Robertson
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Amy R
AR
Johnson
The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Tara M
TM
Lichtenberg
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
Bradley A
BA
Murray
Division of Endocrinology & Metabolism, Department of Medicine, University of Florida College of Medicine & Malcom Randall VA Medical Center, Gainesville, FL 32608, USA.
Hans K
HK
Ghayee
Division of Metabolism, Endocrinology, & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
Tobias
T
Else
University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Shiyun
S
Ling
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Stuart R
SR
Jefferys
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Aguirre A
AA
de Cubas
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Brandon
B
Wenz
Department of Pathology, Erasmus MC University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Esther
E
Korpershoek
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Antonio L
AL
Amelio
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Liza
L
Makowski
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
W Kimryn
WK
Rathmell
INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France.
Anne-Paule
AP
Gimenez-Roqueplo
Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
Thomas J
TJ
Giordano
Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 2C4, Canada.
Sylvia L
SL
Asa
Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA 02111, USA.
Arthur S
AS
Tischler
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA. Electronic address: karel@mail.nih.gov.
Karel
K
Pacak
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: knathans@exchange.upenn.edu.
Katherine L
KL
Nathanson
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: mdwilkerson@outlook.com.
Matthew D
MD
Wilkerson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D050939:Gene Fusion; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010235:Paraganglioma / Q000209:etiology / Q000235:genetics*; D010673:Pheochromocytoma / Q000209:etiology / Q000235:genetics*; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics
C079950:CSDE1 protein, human; D004268:DNA-Binding Proteins; C471298:MAML3 protein, human; D009687:Nuclear Proteins; D035463:Pol1 Transcription Initiation Complex Proteins; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C063844:transcription factor UBF; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
CSDE1; MAML3; TCGA; expression subtypes; genomics; metastasis; molecular profiling; paraganglioma; pheochromocytoma; sequencing