Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
Year: 2018
Type: article
Study design: Observational Study
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 ASCL1 high / DLL3 high / NOTCH low , type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1 low / DLL3 low / NOTCH high , 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.
Source: Nature Communications
Authors: 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, 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, Roman K. Thomas
Institutions: University of Cologne, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, Penn State Milton S. Hershey Medical Center, University of California San Diego, Moores Cancer Center, Centre international de recherche sur le cancer, Max Planck Institute for Molecular Genetics, La Ligue Contre le Cancer, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalier Universitaire de Grenoble, Université Grenoble Alpes, Federal Office of Administration, University Hospital Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Institut pour l'avancée des biosciences, Centre Léon Bérard, University Hospital Zurich, University of Zurich, Oslo University Hospital, University of Oslo, Peter MacCallum Cancer Centre, St Vincent's Hospital Melbourne, Fondazione IRCCS Istituto Nazionale dei Tumori, Jena University Hospital, Friedrich Schiller University Jena, Zentralklinik Bad Berka, Research Center Borstel - Leibniz Lung Center, Memorial Sloan Kettering Cancer Center, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung
Language: English
Topic: Lung Cancer Research Studies
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Energy, World Health Organization, International Association for the Study of Lung Cancer, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Universität zu Köln, Deutschen Konsortium für Translationale Krebsforschung, National Institutes of Health, National Nuclear Security Administration, National Cancer Institute, Los Alamos National Laboratory
Awards: G2134221943, G286898171, G2980544840, G310521049, G3700687868, G4169061630, G4844714250, G5594940513, G5657628048, G5713387433, Verbundprojekt: Systemische Analyse von Modulatoren der onkogenen Signalübertragung - SMOOSE - Anteil Universität Köln, G7209762492, G75892134, G7781679660, 'Juniorverbünde in der Systemmedizin': Multidisziplinärer Ansatz zur Identifizierung tumorspezifischer Signalwegsabhängigkeiten (MILES), G9000183943, Cancer Center Support Grant
OpenAlex ID: W2792828274