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Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
- George, Julie;
- Walter, Vonn;
- Peifer, Martin;
- Alexandrov, Ludmil B;
- Seidel, Danila;
- Leenders, Frauke;
- Maas, Lukas;
- Müller, Christian;
- Dahmen, Ilona;
- Delhomme, Tiffany M;
- Ardin, Maude;
- Leblay, Noemie;
- Byrnes, Graham;
- Sun, Ruping;
- De Reynies, Aurélien;
- McLeer-Florin, Anne;
- Bosco, Graziella;
- Malchers, Florian;
- Menon, Roopika;
- Altmüller, Janine;
- Becker, Christian;
- Nürnberg, Peter;
- Achter, Viktor;
- Lang, Ulrich;
- Schneider, Peter M;
- Bogus, Magdalena;
- Soloway, Matthew G;
- Wilkerson, Matthew D;
- Cun, Yupeng;
- McKay, James D;
- Moro-Sibilot, Denis;
- Brambilla, Christian G;
- Lantuejoul, Sylvie;
- Lemaitre, Nicolas;
- Soltermann, Alex;
- Weder, Walter;
- Tischler, Verena;
- Brustugun, Odd Terje;
- Lund-Iversen, Marius;
- Helland, Åslaug;
- Solberg, Steinar;
- Ansén, Sascha;
- Wright, Gavin;
- Solomon, Benjamin;
- Roz, Luca;
- Pastorino, Ugo;
- Petersen, Iver;
- Clement, Joachim H;
- Sänger, Jörg;
- Wolf, Jürgen;
- Vingron, Martin;
- Zander, Thomas;
- Perner, Sven;
- Travis, William D;
- Haas, Stefan A;
- Olivier, Magali;
- Foll, Matthieu;
- Büttner, Reinhard;
- Hayes, David Neil;
- Brambilla, Elisabeth;
- Fernandez-Cuesta, Lynnette;
- Thomas, Roman K
- et al.
Published Web Location
https://doi.org/10.1038/s41467-018-03099-xAbstract
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.
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