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

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 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, Martin Vingron, Thomas Zander, Sven Perner, William D. Travis, Stefan A. Haas, Magali Olivier, Matthieu Foll, Reinhard Büttner, David Neil Hayes, Elisabeth Brambilla (), Lynnette Fernandez-Cuesta and Roman K. Thomas ()
Additional contact information
Julie George: University of Cologne
Vonn Walter: University of North Carolina at Chapel Hill
Martin Peifer: University of Cologne
Ludmil B. Alexandrov: University of California
Danila Seidel: University of Cologne
Frauke Leenders: University of Cologne
Lukas Maas: University of Cologne
Christian Müller: University of Cologne
Ilona Dahmen: University of Cologne
Tiffany M. Delhomme: International Agency for Research on Cancer (IARC-WHO)
Maude Ardin: International Agency for Research on Cancer (IARC-WHO)
Noemie Leblay: International Agency for Research on Cancer (IARC-WHO)
Graham Byrnes: International Agency for Research on Cancer (IARC-WHO)
Ruping Sun: Max Planck Institute for Molecular Genetics
Aurélien Reynies: Ligue Nationale Contre le Cancer
Anne McLeer-Florin: CHU Grenoble Alpes, UGA/INSERM U1209/CNRS
Graziella Bosco: University of Cologne
Florian Malchers: University of Cologne
Roopika Menon: NEO New Oncology GmbH
Janine Altmüller: University of Cologne
Christian Becker: University of Cologne
Peter Nürnberg: University of Cologne
Viktor Achter: University of Cologne
Ulrich Lang: University of Cologne
Peter M. Schneider: University Hospital Cologne
Magdalena Bogus: University Hospital Cologne
Matthew G. Soloway: University of North Carolina at Chapel Hill
Matthew D. Wilkerson: The University of North Carolina at Chapel Hill
Yupeng Cun: University of Cologne
James D. McKay: International Agency for Research on Cancer (IARC-WHO)
Denis Moro-Sibilot: University Grenoble Alpes, Institute of Advanced Biosciences (IAB), 38043
Christian G. Brambilla: University Grenoble Alpes, Institute of Advanced Biosciences (IAB), 38043
Sylvie Lantuejoul: University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043
Nicolas Lemaitre: University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043
Alex Soltermann: University Hospital Zurich
Walter Weder: University Hospital Zurich
Verena Tischler: University Hospital Zurich
Odd Terje Brustugun: University of Oslo
Marius Lund-Iversen: Oslo University Hospital
Åslaug Helland: University Hospital Zurich
Steinar Solberg: Oslo University Hospital
Sascha Ansén: University Hospital Cologne
Gavin Wright: St. Vincent’s Hospital, Peter MacCallum Cancer Centre
Benjamin Solomon: Peter MacCallum Cancer Centre
Luca Roz: Fondazione IRCCS—Istituto Nazionale Tumori
Ugo Pastorino: Fondazione IRCCS Istituto Nazionale Tumori
Iver Petersen: Friedrich-Schiller-University
Joachim H. Clement: Friedrich-Schiller-University
Jörg Sänger: Institute for Pathology Bad Berka
Jürgen Wolf: University Hospital Cologne
Martin Vingron: Max Planck Institute for Molecular Genetics
Thomas Zander: University Hospital of Cologne
Sven Perner: Leibniz Center for Medicine and Biosciences
William D. Travis: Memorial Sloan-Kettering Cancer Center
Stefan A. Haas: Max Planck Institute for Molecular Genetics
Magali Olivier: International Agency for Research on Cancer (IARC-WHO)
Matthieu Foll: International Agency for Research on Cancer (IARC-WHO)
Reinhard Büttner: University Hospital Cologne
David Neil Hayes: University of North Carolina at Chapel Hill
Elisabeth Brambilla: University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043
Lynnette Fernandez-Cuesta: University of Cologne
Roman K. Thomas: University of Cologne

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03099-x

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