Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors Journal Article
| Authors: | 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, Å; Solberg, S.; Ansén, S.; Wright, G.; Solomon, B.; Roz, L.; Pastorino, U.; Petersen, I.; Clement, J. H.; Sänger, J.; Wolf, J.; Vingron, M.; Zander, T.; Perner, S.; Travis, W. D.; Haas, S. A.; Olivier, M.; Foll, M.; Büttner, R.; Hayes, D. N.; Brambilla, E.; Fernandez-Cuesta, L.; Thomas, R. K. |
| Article Title: | Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors |
| 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. © 2018 The Author(s). |
| Keywords: | allele; gene expression; enzyme activity; immune response; molecular analysis; genomics; tumor; genetic marker; cell |
| Journal Title: | Nature Communications |
| Volume: | 9 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-03-13 |
| Start Page: | 1048 |
| Language: | English |
| DOI: | 10.1038/s41467-018-03099-x |
| PROVIDER: | scopus |
| PMCID: | PMC5849599 |
| PUBMED: | 29535388 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 April 2018 -- Source: Scopus |
