Skip to main content
eScholarship
Open Access Publications from the University of California

UC San Diego

UC San Diego Previously Published Works bannerUC San Diego

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.
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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View