Abstract

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.

Details

Title
Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
Author
George, Julie 1 ; Vonn Walter 2 ; Peifer, Martin 3   VIAFID ORCID Logo  ; Alexandrov, Ludmil B 4   VIAFID ORCID Logo  ; Seidel, Danila 1 ; Leenders, Frauke 1 ; Maas, Lukas 1 ; Müller, Christian 1 ; Dahmen, Ilona 1 ; Delhomme, Tiffany M 5 ; Ardin, Maude 6 ; Leblay, Noemie 5 ; Byrnes, Graham 7 ; Sun, Ruping 8   VIAFID ORCID Logo  ; De Reynies, Aurélien 9 ; McLeer-Florin, Anne 10 ; Bosco, Graziella 1 ; Malchers, Florian 1 ; Menon, Roopika 11 ; Altmüller, Janine 12 ; Becker, Christian 13 ; Nürnberg, Peter 14 ; Achter, Viktor 15 ; Lang, Ulrich 16 ; Schneider, Peter M 17   VIAFID ORCID Logo  ; Bogus, Magdalena 17 ; Soloway, Matthew G 18 ; Wilkerson, Matthew D 19 ; Cun, Yupeng 3   VIAFID ORCID Logo  ; McKay, James D 5 ; Moro-Sibilot, Denis 20 ; Brambilla, Christian G 20 ; Lantuejoul, Sylvie 21 ; Lemaitre, Nicolas 22 ; Soltermann, Alex 23 ; Weder, Walter 24 ; Tischler, Verena 23 ; Brustugun, Odd Terje 25 ; Lund-Iversen, Marius 26 ; Helland, Åslaug 27 ; Solberg, Steinar 28 ; Ansén, Sascha 29 ; Wright, Gavin 30   VIAFID ORCID Logo  ; Solomon, Benjamin 31 ; Luca Roz 32 ; Pastorino, Ugo 33 ; Petersen, Iver 34 ; Clement, Joachim H 35 ; Sänger, Jörg 36 ; Wolf, Jürgen 29 ; Vingron, Martin 8   VIAFID ORCID Logo  ; Zander, Thomas 37 ; Perner, Sven 38 ; Travis, William D 39 ; Haas, Stefan A 8 ; Olivier, Magali 6 ; Foll, Matthieu 5 ; Büttner, Reinhard 40 ; Hayes, David Neil 18 ; Brambilla, Elisabeth 22 ; Fernandez-Cuesta, Lynnette 41 ; Thomas, Roman K 42 

 Department of Translational Genomics, Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne, Cologne, Germany 
 UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Biochemistry and Molecular Biology, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, USA 
 Department of Translational Genomics, Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany 
 Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, San Diego, CA, USA 
 Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer (IARC-WHO), Lyon, France 
 Molecular Mechanisms and Biomarkers Group, Section of Mechanisms of Carcinogenesis, International Agency for Research on Cancer (IARC-WHO), Lyon, France 
 Section of Environment and Radiation, International Agency for Research on Cancer (IARC-WHO), Lyon, France 
 Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, Berlin, Germany 
 Programme Cartes d’Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France 
10  CHU Grenoble Alpes, UGA/INSERM U1209/CNRS, Grenoble, France 
11  NEO New Oncology GmbH, Cologne, Germany 
12  Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; Institute of Human Genetics, University Hospital Cologne, Cologne, Germany 
13  Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany 
14  Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany 
15  Computing Center, University of Cologne, Cologne, Germany 
16  Computing Center, University of Cologne, Cologne, Germany; Department of Informatics, University of Cologne, Cologne, Germany 
17  Institute of Legal Medicine, University Hospital Cologne, Cologne, Germany 
18  UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 
19  Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, NC, USA 
20  CHUGA Grenoble, INSERM U 1209, University Grenoble Alpes, Institute of Advanced Biosciences (IAB), 38043, Grenoble, France 
21  Department of Pathology, CHUGA, INSERM U 1209, University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043, Grenoble, France; Department of Biopathology, Centre Léon Bérard UNICANCER, Lyon, France 
22  Department of Pathology, CHUGA, INSERM U 1209, University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043, Grenoble, France 
23  Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland 
24  Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland 
25  Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 
26  Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 
27  Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway 
28  Department of Thoracic Surgery, Rikshospitalet, Oslo University Hospital, Oslo, Norway 
29  Department of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Germany 
30  Department of Surgery, St. Vincent’s Hospital, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 
31  Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 
32  Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS—Istituto Nazionale Tumori, Milan, Italy 
33  Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy 
34  Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany 
35  Department of Internal Medicine II, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany 
36  Institute for Pathology Bad Berka, Bad Berka, Germany 
37  Gastrointestinal Cancer Group Cologne, Center of Integrated Oncology Cologne–Bonn, Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany; Department of Pathology, University Hospital Cologne, Cologne, Germany 
38  Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany 
39  Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 
40  Department of Pathology, University Hospital Cologne, Cologne, Germany 
41  Department of Translational Genomics, Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne, Cologne, Germany; Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer (IARC-WHO), Lyon, France 
42  Department of Translational Genomics, Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne, Cologne, Germany; Department of Pathology, University Hospital Cologne, Cologne, Germany; German Cancer Research Center, German Cancer Consortium (DKTK), 69120 Heidelberg, Germany 
Pages
1-13
Publication year
2018
Publication date
Mar 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2013631083
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.