Format

Send to

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

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma.

Collaborators (207)

Akbani R, Ally A, Amar L, Amelio AL, Arachchi H, Asa SL, Auchus RJ, Auman JT, Baertsch R, Balasundaram M, Balu S, Bartsch DK, Baudin E, Bauer T, Beaver A, Benz C, Beroukhim R, Beuschlein F, Bodenheimer T, Boice L, Bowen J, Bowlby R, Brooks D, Carlsen R, Carter S, Cassol CA, Cherniack AD, Chin L, Cho J, Chuah E, Chudamani S, Cope L, Crain D, Curley E, Danilova L, de Cubas AA, de Krijger RR, Demchok JA, Deutschbein T, Dhalla N, Dimmock D, Dinjens WN, Else T, Eng C, Eschbacher J, Fassnacht M, Felau I, Feldman M, Ferguson ML, Fiddes I, Fishbein L, Frazer S, Gabriel SB, Gardner J, Gastier-Foster JM, Gehlenborg N, Gerken M, Getz G, Geurts J, Ghayee HK, Gimenez-Roqueplo AP, Giordano TJ, Goldman M, Graim K, Gupta M, Haan D, Hahner S, Hantel C, Haussler D, Hayes DN, Heiman DI, Hoadley KA, Holt RA, Hoyle AP, Huang M, Hunt B, Hutter CM, Jefferys SR, Johnson AR, Jones SJ, Jones CD, Kasaian K, Kebebew E, Kim J, Kimes P, Knijnenburg T, Korpershoek E, Lander E, Lawrence MS, Lechan R, Lee D, Leraas KM, Lerario A, Leshchiner I, Lichtenberg TM, Lin P, Ling S, Liu J, LiVolsi VA, Lolla L, Lotan Y, Lu Y, Ma Y, Maison N, Makowski L, Mallery D, Mannelli M, Marquard J, Marra MA, Matthew T, Mayo M, Méatchi T, Meng S, Merino MJ, Mete O, Meyerson M, Mieczkowski PA, Mills GB, Moore RA, Morozova O, Morris S, Mose LE, Mungall AJ, Murray BA, Naresh R, Nathanson KL, Newton Y, Ng S, Ni Y, Noble MS, Nwariaku F, Pacak K, Parker JS, Paul E, Penny R, Perou CM, Perou AH, Pihl T, Powers J, Rabaglia J, Radenbaugh A, Ramirez NC, Rao A, Rathmell WK, Riester A, Roach J, Robertson AG, Sadeghi S, Saksena G, Salama S, Saller C, Sandusky G, Sbiera S, Schein JE, Schumacher SE, Shelton C, Shelton T, Sheth M, Shi Y, Shih J, Shmulevich I, Simons JV, Sipahimalani P, Skelly T, Sofia HJ, Sokolov A, Soloway MG, Sougnez C, Stuart J, Sun C, Swatloski T, Tam A, Tan D, Tarnuzzer R, Tarvin K, Thiessen N, Thorne LB, Timmers HJ, Tischler AS, Tse K, Uzunangelov V, van Berkel A, Veluvolu U, Vicha A, Voet D, Waldmann J, Walter V, Wan Y, Wang Z, Wang TS, Weaver J, Weinstein JN, Weismann D, Wenz B, Wilkerson MD, Wise L, Wong T, Wong C, Wu Y, Yang L, Zelinka T, Zenklusen JC, Zhang JJ, Zhang W, Zhu J, Zinzindohoué F, Zmuda E.

Author information

1
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
2
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
3
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
4
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA.
5
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
6
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
7
The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
8
Division of Endocrinology & Metabolism, Department of Medicine, University of Florida College of Medicine & Malcom Randall VA Medical Center, Gainesville, FL 32608, USA.
9
Division of Metabolism, Endocrinology, & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
10
University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
11
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.
12
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
13
Department of Pathology, Erasmus MC University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
14
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.
15
INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France.
16
Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
17
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.
18
Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA 02111, USA.
19
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.
20
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.
21
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.

Abstract

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

PMID:
28162975
PMCID:
PMC5643159
DOI:
10.1016/j.ccell.2017.01.001
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center