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

George, J.; Walter, V.; Peifer, M.; Alexandrov, L. B.; Seidel, D.; Leenders, F.; Maas, L.; Müller, C.; Dahmen, I.; Delhomme, T. M.; Ardin, M.; Leblay, N.; Byrnes, G.; Sun, R.; De Reynies, A.; McLeer-Florin, A.; Bosco, G.; Malchers, F.; Menon, R.; Altmüller, J.; Becker, C.; Nürnberg, P.; Achter, V.; Lang, U.; Schneider, P. M.; Bogus, M.; Soloway, M. G.; Wilkerson, M. D.; Cun, Y.; McKay, J. D.; Moro-Sibilot, D.; Brambilla, C. G.; Lantuejoul, S.; Lemaitre, N.; Soltermann, A.; Weder, W.; Tischler, V.; Brustugun, O. T.; Lund-Iversen, M.; Helland, A.; Solberg, S.; Ansen, S.; Wright, G.; Solomon, B.; Roz, L.; Pastorino, U.; Petersen, I.; Clement, J. H.; Sanger, J.; Wolf, J.; Vingron, Martin; Zander, T.; Perner, S.; Travis, W. D.; Haas, S. A.; Olivier, M.; Foll, M.; Buttner, R.; Hayes, D. N.; Brambilla, E.; Fernandez-Cuesta, L.; Thomas, R. K.

doi:10.1038/s41467-018-03099-x

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

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Vingron, Martin
Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Haas, S. A.
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

George, J., Walter, V., Peifer, M., Alexandrov, L. B., Seidel, D., Leenders, F., et al. (2018). Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nature Communications, 9(1): 1048. doi:10.1038/s41467-018-03099-x.

Cite as: https://hdl.handle.net/21.11116/0000-0003-7405-5

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 ASCL1(high)/DLL3(high)/NOTCH(low), type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1(low)/DLL3(low)/NOTCH(high), 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.