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  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., 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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-7405-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-7406-4
Genre: Journal Article

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George, J., Author
Walter, V., Author
Peifer, M., Author
Alexandrov, L. B., Author
Seidel, D., Author
Leenders, F., Author
Maas, L., Author
Müller, C., Author
Dahmen, I., Author
Delhomme, T. M., Author
Ardin, M., Author
Leblay, N., Author
Byrnes, G., Author
Sun, R., Author
De Reynies, A., Author
McLeer-Florin, A., Author
Bosco, G., Author
Malchers, F., Author
Menon, R., Author
Altmüller, J., Author
Becker, C., AuthorNürnberg, P., AuthorAchter, V., AuthorLang, U., AuthorSchneider, P. M., AuthorBogus, M., AuthorSoloway, M. G., AuthorWilkerson, M. D., AuthorCun, Y., AuthorMcKay, J. D., AuthorMoro-Sibilot, D., AuthorBrambilla, C. G., AuthorLantuejoul, S., AuthorLemaitre, N., AuthorSoltermann, A., AuthorWeder, W., AuthorTischler, V., AuthorBrustugun, O. T., AuthorLund-Iversen, M., AuthorHelland, A., AuthorSolberg, S., AuthorAnsen, S., AuthorWright, G., AuthorSolomon, B., AuthorRoz, L., AuthorPastorino, U., AuthorPetersen, I., AuthorClement, J. H., AuthorSanger, J., AuthorWolf, J., AuthorVingron, Martin1, Author              Zander, T., AuthorPerner, S., AuthorTravis, W. D., AuthorHaas, S. A.2, Author              Olivier, M., AuthorFoll, M., AuthorButtner, R., AuthorHayes, D. N., AuthorBrambilla, E., AuthorFernandez-Cuesta, L., AuthorThomas, R. K., Author more..
Affiliations:
1Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              
2Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              

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Free keywords: Carcinoma, Neuroendocrine/*genetics Carcinoma, Non-Small-Cell Lung/*genetics DNA Mutational Analysis Genomics/methods High-Throughput Nucleotide Sequencing Humans Immunohistochemistry In Situ Hybridization, Fluorescence In Vitro Techniques Lung Neoplasms/genetics Neuroendocrine Tumors/*genetics Small Cell Lung Carcinoma/*genetics
 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.

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Language(s): eng - English
 Dates: 2018-01-182018-03-13
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/s41467-018-03099-x
ISSN: 2041-1723 (Electronic)2041-1723 (Print)
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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 9 (1) Sequence Number: 1048 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723