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

  • Author(s): 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.

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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