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Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

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 LCN...

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Autores principales: George, Julie, Walter, Vonn, Peifer, Martin, Alexandrov, Ludmil B., Seidel, Danila, Leenders, Frauke, Maas, Lukas, Müller, Christian, Dahmen, Ilona, Delhomme, Tiffany M., Ardin, Maude, Leblay, Noemie, Byrnes, Graham, Sun, Ruping, De Reynies, Aurélien, McLeer-Florin, Anne, Bosco, Graziella, Malchers, Florian, Menon, Roopika, Altmüller, Janine, Becker, Christian, Nürnberg, Peter, Achter, Viktor, Lang, Ulrich, Schneider, Peter M., Bogus, Magdalena, Soloway, Matthew G., Wilkerson, Matthew D., Cun, Yupeng, McKay, James D., Moro-Sibilot, Denis, Brambilla, Christian G., Lantuejoul, Sylvie, Lemaitre, Nicolas, Soltermann, Alex, Weder, Walter, Tischler, Verena, Brustugun, Odd Terje, Lund-Iversen, Marius, Helland, Åslaug, Solberg, Steinar, Ansén, Sascha, Wright, Gavin, Solomon, Benjamin, Roz, Luca, Pastorino, Ugo, Petersen, Iver, Clement, Joachim H., Sänger, Jörg, Wolf, Jürgen, Vingron, Martin, Zander, Thomas, Perner, Sven, Travis, William D., Haas, Stefan A., Olivier, Magali, Foll, Matthieu, Büttner, Reinhard, Hayes, David Neil, Brambilla, Elisabeth, Fernandez-Cuesta, Lynnette, Thomas, Roman K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849599/
https://www.ncbi.nlm.nih.gov/pubmed/29535388
http://dx.doi.org/10.1038/s41467-018-03099-x
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author George, Julie
Walter, Vonn
Peifer, Martin
Alexandrov, Ludmil B.
Seidel, Danila
Leenders, Frauke
Maas, Lukas
Müller, Christian
Dahmen, Ilona
Delhomme, Tiffany M.
Ardin, Maude
Leblay, Noemie
Byrnes, Graham
Sun, Ruping
De Reynies, Aurélien
McLeer-Florin, Anne
Bosco, Graziella
Malchers, Florian
Menon, Roopika
Altmüller, Janine
Becker, Christian
Nürnberg, Peter
Achter, Viktor
Lang, Ulrich
Schneider, Peter M.
Bogus, Magdalena
Soloway, Matthew G.
Wilkerson, Matthew D.
Cun, Yupeng
McKay, James D.
Moro-Sibilot, Denis
Brambilla, Christian G.
Lantuejoul, Sylvie
Lemaitre, Nicolas
Soltermann, Alex
Weder, Walter
Tischler, Verena
Brustugun, Odd Terje
Lund-Iversen, Marius
Helland, Åslaug
Solberg, Steinar
Ansén, Sascha
Wright, Gavin
Solomon, Benjamin
Roz, Luca
Pastorino, Ugo
Petersen, Iver
Clement, Joachim H.
Sänger, Jörg
Wolf, Jürgen
Vingron, Martin
Zander, Thomas
Perner, Sven
Travis, William D.
Haas, Stefan A.
Olivier, Magali
Foll, Matthieu
Büttner, Reinhard
Hayes, David Neil
Brambilla, Elisabeth
Fernandez-Cuesta, Lynnette
Thomas, Roman K.
author_facet George, Julie
Walter, Vonn
Peifer, Martin
Alexandrov, Ludmil B.
Seidel, Danila
Leenders, Frauke
Maas, Lukas
Müller, Christian
Dahmen, Ilona
Delhomme, Tiffany M.
Ardin, Maude
Leblay, Noemie
Byrnes, Graham
Sun, Ruping
De Reynies, Aurélien
McLeer-Florin, Anne
Bosco, Graziella
Malchers, Florian
Menon, Roopika
Altmüller, Janine
Becker, Christian
Nürnberg, Peter
Achter, Viktor
Lang, Ulrich
Schneider, Peter M.
Bogus, Magdalena
Soloway, Matthew G.
Wilkerson, Matthew D.
Cun, Yupeng
McKay, James D.
Moro-Sibilot, Denis
Brambilla, Christian G.
Lantuejoul, Sylvie
Lemaitre, Nicolas
Soltermann, Alex
Weder, Walter
Tischler, Verena
Brustugun, Odd Terje
Lund-Iversen, Marius
Helland, Åslaug
Solberg, Steinar
Ansén, Sascha
Wright, Gavin
Solomon, Benjamin
Roz, Luca
Pastorino, Ugo
Petersen, Iver
Clement, Joachim H.
Sänger, Jörg
Wolf, Jürgen
Vingron, Martin
Zander, Thomas
Perner, Sven
Travis, William D.
Haas, Stefan A.
Olivier, Magali
Foll, Matthieu
Büttner, Reinhard
Hayes, David Neil
Brambilla, Elisabeth
Fernandez-Cuesta, Lynnette
Thomas, Roman K.
author_sort George, Julie
collection PubMed
description 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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spelling pubmed-58495992018-03-15 Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors George, Julie Walter, Vonn Peifer, Martin Alexandrov, Ludmil B. Seidel, Danila Leenders, Frauke Maas, Lukas Müller, Christian Dahmen, Ilona Delhomme, Tiffany M. Ardin, Maude Leblay, Noemie Byrnes, Graham Sun, Ruping De Reynies, Aurélien McLeer-Florin, Anne Bosco, Graziella Malchers, Florian Menon, Roopika Altmüller, Janine Becker, Christian Nürnberg, Peter Achter, Viktor Lang, Ulrich Schneider, Peter M. Bogus, Magdalena Soloway, Matthew G. Wilkerson, Matthew D. Cun, Yupeng McKay, James D. Moro-Sibilot, Denis Brambilla, Christian G. Lantuejoul, Sylvie Lemaitre, Nicolas Soltermann, Alex Weder, Walter Tischler, Verena Brustugun, Odd Terje Lund-Iversen, Marius Helland, Åslaug Solberg, Steinar Ansén, Sascha Wright, Gavin Solomon, Benjamin Roz, Luca Pastorino, Ugo Petersen, Iver Clement, Joachim H. Sänger, Jörg Wolf, Jürgen Vingron, Martin Zander, Thomas Perner, Sven Travis, William D. Haas, Stefan A. Olivier, Magali Foll, Matthieu Büttner, Reinhard Hayes, David Neil Brambilla, Elisabeth Fernandez-Cuesta, Lynnette Thomas, Roman K. Nat Commun Article 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. Nature Publishing Group UK 2018-03-13 /pmc/articles/PMC5849599/ /pubmed/29535388 http://dx.doi.org/10.1038/s41467-018-03099-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
George, Julie
Walter, Vonn
Peifer, Martin
Alexandrov, Ludmil B.
Seidel, Danila
Leenders, Frauke
Maas, Lukas
Müller, Christian
Dahmen, Ilona
Delhomme, Tiffany M.
Ardin, Maude
Leblay, Noemie
Byrnes, Graham
Sun, Ruping
De Reynies, Aurélien
McLeer-Florin, Anne
Bosco, Graziella
Malchers, Florian
Menon, Roopika
Altmüller, Janine
Becker, Christian
Nürnberg, Peter
Achter, Viktor
Lang, Ulrich
Schneider, Peter M.
Bogus, Magdalena
Soloway, Matthew G.
Wilkerson, Matthew D.
Cun, Yupeng
McKay, James D.
Moro-Sibilot, Denis
Brambilla, Christian G.
Lantuejoul, Sylvie
Lemaitre, Nicolas
Soltermann, Alex
Weder, Walter
Tischler, Verena
Brustugun, Odd Terje
Lund-Iversen, Marius
Helland, Åslaug
Solberg, Steinar
Ansén, Sascha
Wright, Gavin
Solomon, Benjamin
Roz, Luca
Pastorino, Ugo
Petersen, Iver
Clement, Joachim H.
Sänger, Jörg
Wolf, Jürgen
Vingron, Martin
Zander, Thomas
Perner, Sven
Travis, William D.
Haas, Stefan A.
Olivier, Magali
Foll, Matthieu
Büttner, Reinhard
Hayes, David Neil
Brambilla, Elisabeth
Fernandez-Cuesta, Lynnette
Thomas, Roman K.
Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
title Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
title_full Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
title_fullStr Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
title_full_unstemmed Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
title_short Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
title_sort integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849599/
https://www.ncbi.nlm.nih.gov/pubmed/29535388
http://dx.doi.org/10.1038/s41467-018-03099-x
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