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PMID: 28162975 Published · ppublish English Journal Article

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma.

Cancer cell ·Vol. 31 ·No. 2 ·2017-00-13 ·Pages 181-193

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

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

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,genetics Pheochromocytoma/etiology,genetics Pol1 Transcription Initiation Complex Proteins/genetics Proto-Oncogene Proteins c-ret/genetics RNA-Binding Proteins/genetics Trans-Activators Transcription Factors/genetics

Chemicals

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

Authors & Affiliations

26 authors, click to expand affiliations / ORCID

Fishbein Lauren

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

Leshchiner Ignaty

The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Walter Vonn

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Danilova Ludmila

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA.

Robertson A Gordon

Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.

Johnson Amy R

Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Lichtenberg Tara M

The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.

Murray Bradley A

The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Ghayee Hans K

Division of Endocrinology & Metabolism, Department of Medicine, University of Florida College of Medicine & Malcom Randall VA Medical Center, Gainesville, FL 32608, USA.

Else Tobias

Division of Metabolism, Endocrinology, & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.

Ling Shiyun

University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Jefferys Stuart R

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

de Cubas Aguirre A

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.

Wenz Brandon

Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

Korpershoek Esther

Department of Pathology, Erasmus MC University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.

Amelio Antonio L

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Makowski Liza

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.

Rathmell W Kimryn

Gimenez-Roqueplo Anne-Paule

INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France.

Giordano Thomas J

Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109, USA.

Asa Sylvia L

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.

Tischler Arthur S

Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA 02111, USA.

Cancer Genome Atlas Research Network

Pacak Karel

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.

Nathanson Katherine L

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.

Wilkerson Matthew D

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.

Investigators

207 investigators, click to expand

Akbani Rehan

Ally Adrian

Amar Laurence

Amelio Antonio L

Arachchi Harindra

Asa Sylvia L

Auchus Richard J

Auman J Todd

Baertsch Robert

Balasundaram Miruna

Balu Saianand

Bartsch Detlef K

Baudin Eric

Bauer Thomas

Beaver Allison

Benz Christopher

Beroukhim Rameen

Beuschlein Felix

Bodenheimer Tom

Boice Lori

Bowen Jay

Bowlby Reanne

Brooks Denise

Carlsen Rebecca

Carter Suzie

Cassol Clarissa A

Cherniack Andrew D

Chin Lynda

Cho Juok

Chuah Eric

Chudamani Sudha

Cope Leslie

Crain Daniel

Curley Erin

Danilova Ludmila

de Cubas Aguirre A

de Krijger Ronald R

Demchok John A

Deutschbein Timo

Dhalla Noreen

Dimmock David

Dinjens Winand N M

Else Tobias

Eng Charis

Eschbacher Jennifer

Fassnacht Martin

Felau Ina

Feldman Michael

Ferguson Martin L

Fiddes Ian

Fishbein Lauren

Frazer Scott

Gabriel Stacey B

Gardner Johanna

Gastier-Foster Julie M

Gehlenborg Nils

Gerken Mark

Getz Gad

Geurts Jennifer

Ghayee Hans K

Gimenez-Roqueplo Anne-Paule

Giordano Thomas J

Goldman Mary

Graim Kiley

Gupta Manaswi

Haan David

Hahner Stefanie

Hantel Constanze

Haussler David

Hayes D Neil

Heiman David I

Hoadley Katherine A

Holt Robert A

Hoyle Alan P

Huang Mei

Hunt Bryan

Hutter Carolyn M

Jefferys Stuart R

Johnson Amy R

Jones Steven J M

Jones Corbin D

Kasaian Katayoon

Kebebew Electron

Kim Jaegil

Kimes Patrick

Knijnenburg Theo

Korpershoek Esther

Lander Eric

Lawrence Michael S

Lechan Ronald

Lee Darlene

Leraas Kristen M

Lerario Antonio

Leshchiner Ignaty

Lichtenberg Tara M

Lin Pei

Ling Shiyun

Liu Jia

LiVolsi Virginia A

Lolla Laxmi

Lotan Yair

Lu Yiling

Ma Yussanne

Maison Nicole

Makowski Liza

Mallery David

Mannelli Massimo

Marquard Jessica

Marra Marco A

Matthew Thomas

Mayo Michael

Méatchi Tchao

Meng Shaowu

Merino Maria J

Mete Ozgur

Meyerson Matthew

Mieczkowski Piotr A

Mills Gordon B

Moore Richard A

Morozova Olena

Morris Scott

Mose Lisle E

Mungall Andrew J

Murray Bradley A

Naresh Rashi

Nathanson Katherine L

Newton Yulia

Ng Sam

Ni Ying

Noble Michael S

Nwariaku Fiemu

Pacak Karel

Parker Joel S

Paul Evan

Penny Robert

Perou Charles M

Perou Amy H

Pihl Todd

Powers James

Rabaglia Jennifer

Radenbaugh Amie

Ramirez Nilsa C

Rao Arjun

Rathmell W Kimryn

Riester Anna

Roach Jeffrey

Robertson A Gordon

Sadeghi Sara

Saksena Gordon

Salama Sofie

Saller Charles

Sandusky George

Sbiera Silviu

Schein Jacqueline E

Schumacher Steven E

Shelton Candace

Shelton Troy

Sheth Margi

Shi Yan

Shih Juliann

Shmulevich Ilya

Simons Janae V

Sipahimalani Payal

Skelly Tara

Sofia Heidi J

Sokolov Artem

Soloway Matthew G

Sougnez Carrie

Stuart Josh

Sun Charlie

Swatloski Teresa

Tam Angela

Tan Donghui

Tarnuzzer Roy

Tarvin Katherine

Thiessen Nina

Thorne Leigh B

Timmers Henri J

Tischler Arthur S

Tse Kane

Uzunangelov Vlado

van Berkel Anouk

Veluvolu Umadevi

Vicha Ales

Voet Doug

Waldmann Jens

Walter Vonn

Wan Yunhu

Wang Zhining

Wang Tracy S

Weaver Joellen

Weinstein John N

Weismann Dirk

Wenz Brandon

Wilkerson Matthew D

Wise Lisa

Wong Tina

Wong Christopher

Wu Ye

Yang Liming

Zelinka Tomas

Zenklusen Jean C

Zhang Jiashan Julia

Zhang Wei

Zhu Jingchun

Zinzindohoué Franck

Zmuda Erik

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Article Info

Journal

Cancer cell

Abbr.

Cancer Cell

ISSN

1878-3686

DOI

10.1016/j.ccell.2017.01.001

karel@mail.nih.gov
knathans@exchange.upenn.edu
mdwilkerson@outlook.com

Published

2017-00-13

Epub

2017-00-02

Pages

181-193

Language

English

Region

United States

NLM ID

101130617

PMCID

PMC5643159

Subset

Grants

NCI NIH HHS · P30 CA016672 · United States

NCI NIH HHS · U24 CA143882 · United States

NHGRI NIH HHS · U54 HG003067 · United States

NCI NIH HHS · T32 CA009582 · United States

NCI NIH HHS · U24 CA143835 · United States

NCI NIH HHS · U24 CA143866 · United States

NCI NIH HHS · U24 CA210950 · United States

NCI NIH HHS · U24 CA143845 · United States

NCI NIH HHS · U24 CA143799 · United States

NHGRI NIH HHS · U54 HG003273 · United States

NCI NIH HHS · U24 CA144025 · United States

NCI NIH HHS · U24 CA180951 · United States

NCI NIH HHS · U24 CA143840 · United States

NCI NIH HHS · U24 CA143843 · United States

NCI NIH HHS · U24 CA210974 · United States

NCI NIH HHS · U24 CA143858 · United States

NCI NIH HHS · U24 CA143848 · United States

NHGRI NIH HHS · U54 HG003079 · United States

NCI NIH HHS · U24 CA210949 · United States

NCI NIH HHS · U24 CA143883 · United States

NCI NIH HHS · R00 CA157954 · United States

NCI NIH HHS · U24 CA143867 · United States

NCI NIH HHS · U24 CA199461 · United States

External Links

PubMed source DOI: 10.1016/j.ccell.2017.01.001 PMC Full Text View journal details

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