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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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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., 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. 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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