1. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.
- Author
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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, and Thomas, Roman K
- Subjects
Humans ,Neuroendocrine Tumors ,Carcinoma ,Neuroendocrine ,Carcinoma ,Non-Small-Cell Lung ,Lung Neoplasms ,Immunohistochemistry ,In Situ Hybridization ,Fluorescence ,DNA Mutational Analysis ,Genomics ,Small Cell Lung Carcinoma ,High-Throughput Nucleotide Sequencing ,In Vitro Techniques ,Carcinoma ,Neuroendocrine ,Non-Small-Cell Lung ,In Situ Hybridization ,Fluorescence - 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.
- Published
- 2018