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

2018; Nature Portfolio; Volume: 9; Issue: 1 Linguagem: Inglês

10.1038/s41467-018-03099-x

2041-1723

Julie George, Vonn Walter, Martin Peifer, Ludmil B. Alexandrov, Danila Seidel, Frauke Leenders, Lukas Maas, Christian Müller, Ilona Dahmen, Tiffany M. Delhomme, Maude Ardin, Noémie Leblay, Graham Byrnes, Ruping Sun, Aurélien de Reyniès, 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 McKay, Denis Moro‐Sibilot, Christian Brambilla, Sylvie Lantuéjoul, Nicolas Lemaître, 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, D. Neil Hayes, Élisabeth Brambilla, Lynnette Fernández-Cuesta, Roman K. Thomas,

Lung Cancer Treatments and Mutations

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