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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: |
George, J., Walter, V., Peifer, M.  ORCID: https://orcid.org/0000-0002-5243-5503, Alexandrov, L.B. ORCID: https://orcid.org/0000-0003-3596-4515, Seidel, D., Leenders, F., Maas, L., Müller, C., Dahmen, I., Delhomme, T.M., Ardin, M., Leblay, N., Byrnes, G., Sun, R. ORCID: https://orcid.org/0000-0003-3702-9483, De Reynies, A., McLeer-Florin, A., Bosco, G., Malchers, F., Menon, R., Altmüller, J. ORCID: https://orcid.org/0000-0003-4372-1521, Becker, C., Nürnberg, P., Achter, V., Lang, U., Schneider, P.M. ORCID: https://orcid.org/0000-0003-0744-2349, Bogus, M., Soloway, M.G., Wilkerson, M.D., Cun, Y. ORCID: https://orcid.org/0000-0002-4241-8099, 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. ORCID: https://orcid.org/0000-0002-7000-9305, Solomon, B., Roz, L., Pastorino, U., Petersen, I., Clement, J.H., Sänger, J., Wolf, J., Vingron, M. ORCID: https://orcid.org/0000-0002-1765-4241, Zander, T., Perner, S., Travis, W.D., Haas, S.A., Olivier, M., Foll, M., Büttner, R., Hayes, D.N., Brambilla, E., Fernandez-Cuesta, L. and Thomas, R.K.
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| 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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