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| Item Type: | Article |
|---|---|
| Title: | Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors |
| Creators Name: | George, J. and Walter, V. and Peifer, M. and Alexandrov, L.B. and Seidel, D. and Leenders, F. and Maas, L. and Müller, C. and Dahmen, I. and Delhomme, T.M. and Ardin, M. and Leblay, N. and Byrnes, G. and Sun, R. and De Reynies, A. and McLeer-Florin, A. and Bosco, G. and Malchers, F. and Menon, R. and Altmüller, J. and Becker, C. and Nürnberg, P. and Achter, V. and Lang, U. and Schneider, P.M. and Bogus, M. and Soloway, M.G. and Wilkerson, M.D. and Cun, Y. and McKay, J.D. and Moro-Sibilot, D. and Brambilla, C.G. and Lantuejoul, S. and Lemaitre, N. and Soltermann, A. and Weder, W. and Tischler, V. and Brustugun, O.T. and Lund-Iversen, M. and Helland, Å. and Solberg, S. and Ansén, S. and Wright, G. and Solomon, B. and Roz, L. and Pastorino, U. and Petersen, I. and Clement, J.H. and Sänger, J. and Wolf, J. and Vingron, M. and Zander, T. and Perner, S. and Travis, W.D. and Haas, S.A. and Olivier, M. and Foll, M. and Büttner, R. and Hayes, D.N. and Brambilla, E. and Fernandez-Cuesta, L. and Thomas, R.K. |
| 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. |
| Keywords: | Neuroendocrine Carcinoma, Non-Small-Cell Lung Carcinoma, DNA Mutational Analysis, Genomics, High-Throughput Nucleotide Sequencing, Immunohistochemistry, Fluorescence In Situ Hybridization, In Vitro Techniques, Lung Neoplasms, Neuroendocrine Tumors, Small Cell Lung Carcinoma / Genetics |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 9 |
| Number: | 1 |
| Page Range: | 1048 |
| Date: | 13 March 2018 |
| Official Publication: | https://doi.org/10.1038/s41467-018-03099-x |
| PubMed: | View item in PubMed |
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