Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

被引：0

作者：

Julie George

Vonn Walter

Martin Peifer

Ludmil B. Alexandrov

Danila Seidel

Frauke Leenders

Lukas Maas

Christian Müller

Ilona Dahmen

Tiffany M. Delhomme

Maude Ardin

Noemie Leblay

Graham Byrnes

Ruping Sun

Aurélien De Reynies

Anne McLeer-Florin

Graziella Bosco

Florian Malchers

Roopika Menon

Janine Altmüller

Christian Becker

Peter Nürnberg

Viktor Achter

Ulrich Lang

Peter M. Schneider

Magdalena Bogus

Matthew G. Soloway

Matthew D. Wilkerson

Yupeng Cun

James D. McKay

Denis Moro-Sibilot

Christian G. Brambilla

Sylvie Lantuejoul

Nicolas Lemaitre

Alex Soltermann

Walter Weder

Verena Tischler

Odd Terje Brustugun

Marius Lund-Iversen

Åslaug Helland

Steinar Solberg

Sascha Ansén

Gavin Wright

Benjamin Solomon

Luca Roz

Ugo Pastorino

Iver Petersen

Joachim H. Clement

Jörg Sänger

Jürgen Wolf

机构：

[1] University of Cologne,Department of Translational Genomics, Center of Integrated Oncology Cologne–Bonn, Medical Faculty

[2] University of North Carolina at Chapel Hill,UNC Lineberger Comprehensive Cancer Center School of Medicine

[3] 500 University Drive,Department of Biochemistry and Molecular Biology, Penn State Milton S. Hershey Medical Center

[4] University of Cologne,Center for Molecular Medicine Cologne (CMMC)

[5] University of California,Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center

[6] International Agency for Research on Cancer (IARC-WHO),Genetic Cancer Susceptibility Group, Section of Genetics

[7] International Agency for Research on Cancer (IARC-WHO),Molecular Mechanisms and Biomarkers Group, Section of Mechanisms of Carcinogenesis

[8] International Agency for Research on Cancer (IARC-WHO),Section of Environment and Radiation

[9] Max Planck Institute for Molecular Genetics,Computational Molecular Biology Group

[10] Ligue Nationale Contre le Cancer,Programme Cartes d’Identité des Tumeurs (CIT)

[11] CHU Grenoble Alpes,Cologne Center for Genomics (CCG)

[12] UGA/INSERM U1209/CNRS,Institute of Human Genetics

[13] NEO New Oncology GmbH,Cologne Excellence Cluster on Cellular Stress Responses in Aging

[14] University of Cologne,Associated Diseases (CECAD)

[15] University Hospital Cologne,Computing Center

[16] University of Cologne,Department of Informatics

[17] University of Cologne,Institute of Legal Medicine

[18] University of Cologne,Department of Genetics, Lineberger Comprehensive Cancer Center

[19] University Hospital Cologne,CHUGA Grenoble, INSERM U 1209

[20] The University of North Carolina at Chapel Hill,Department of Pathology, CHUGA, INSERM U 1209

[21] University Grenoble Alpes,Department of Biopathology

[22] Institute of Advanced Biosciences (IAB),Institute of Pathology and Molecular Pathology

[23] 38043,Department of Thoracic Surgery

[24] University of Grenobles Alpes,Institute of Clinical Medicine, Faculty of Medicine

[25] Institute of Advanced Biosciences (IAB),Department of Oncology, Norwegian Radium Hospital

[26] 38043,Department of Pathology, Norwegian Radium Hospital

[27] Centre Léon Bérard UNICANCER,Department of Thoracic Surgery, Rikshospitalet

[28] University Hospital Zurich,Department of Internal Medicine, Center of Integrated Oncology Cologne

[29] University Hospital Zurich,Bonn

[30] University of Oslo,Department of Surgery

[31] Oslo University Hospital,Department of Haematology and Medical Oncology

[32] Oslo University Hospital,Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine

[33] Oslo University Hospital,Thoracic Surgery Unit, Department of Surgery

[34] University Hospital Cologne,Institute of Pathology, Jena University Hospital

[35] St. Vincent’s Hospital,Department of Internal Medicine II, Jena University Hospital

[36] Peter MacCallum Cancer Centre,Gastrointestinal Cancer Group Cologne, Center of Integrated Oncology Cologne–Bonn, Department I for Internal Medicine

[37] Peter MacCallum Cancer Centre,Department of Pathology

[38] Fondazione IRCCS—Istituto Nazionale Tumori,Pathology of the University Medical Center Schleswig

[39] Fondazione IRCCS Istituto Nazionale Tumori,Holstein, Campus Luebeck and the Research Center Borstel

[40] Friedrich-Schiller-University,Department of Pathology

[41] Friedrich-Schiller-University,German Cancer Research Center

[42] Institute for Pathology Bad Berka,undefined

[43] University Hospital of Cologne,undefined

[44] University Hospital Cologne,undefined

[45] Leibniz Center for Medicine and Biosciences,undefined

[46] Memorial Sloan-Kettering Cancer Center,undefined

[47] German Cancer Consortium (DKTK),undefined

来源：

Nature Communications | / 9卷

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摘要：

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

引用

共 50 条

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George, Julie
Walter, Vonn
Peifer, Martin
Alexandrov, Ludmil B.
Seidel, Danila
Leenders, Frauke
Maas, Lukas
Mueller, Christian
Dahmen, Ilona
Delhomme, Tiffany M.
Ardin, Maude
Leblay, Noemie
Byrnes, Graham
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