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

Julie George; Vonn Walter; Martin Peifer; Ludmil B. Alexandrov; Danila Seidel; Frauke Leenders; Lukas Maas; Christian Müller; Ilona Dahmen; Tiffany M. Delhomme; Maude Ardin; Noémie Leblay; Graham Byrnes; Ruping Sun; Aurélien de Reyniès; Anne McLeer‐Florin; Graziella Bosco; Florian Malchers; Roopika Menon; Janine Altmüller; Christian Becker; Peter Nürnberg; Viktor Achter; Ulrich Lang; Peter M. Schneider; Magdalena Bogus; Matthew G. Soloway; Matthew D. Wilkerson; Yupeng Cun; James McKay; Denis Moro‐Sibilot; Christian Brambilla; Sylvie Lantuéjoul; Nicolas Lemaître; Alex Soltermann; Walter Weder; Verena Tischler; Odd Terje Brustugun; Marius Lund‐Iversen; Åslaug Helland; Steinar Solberg; Sascha Ansén; Gavin Wright; Benjamin Solomon; Luca Roz; Ugo Pastorino; Iver Petersen; Joachim H. Clement; Jörg Sänger; Jürgen Wolf; Martin Vingron; Thomas Zander; Sven Perner; William D. Travis; Stefan A. Haas; Magali Olivier; Matthieu Foll; Reinhard Büttner; D. Neil Hayes; Élisabeth Brambilla; Lynnette Fernandez‐Cuesta; Roman K. Thomas

doi:10.1038/s41467-018-03099-x

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

Julie George(University of Cologne), Vonn Walter(University of North Carolina at Chapel Hill), Martin Peifer(University of Cologne), Ludmil B. Alexandrov(University of California San Diego), Danila Seidel(University of Cologne), Frauke Leenders(University of Cologne), Lukas Maas(University of Cologne), Christian Müller(University of Cologne), Ilona Dahmen(University of Cologne), Tiffany M. Delhomme(Centre international de recherche sur le cancer), Maude Ardin(Centre international de recherche sur le cancer), Noémie Leblay(Centre international de recherche sur le cancer), Graham Byrnes(Centre international de recherche sur le cancer), Ruping Sun(Max Planck Institute for Molecular Genetics), Aurélien de Reyniès(La Ligue Contre le Cancer), Anne McLeer‐Florin(Centre National de la Recherche Scientifique), Graziella Bosco(University of Cologne), Florian Malchers(University of Cologne), Roopika Menon, Janine Altmüller(University of Cologne), Christian Becker(University of Cologne), Peter Nürnberg(University of Cologne), Viktor Achter(University of Cologne), Ulrich Lang(TH Köln - University of Applied Sciences), Peter M. Schneider(University Hospital Cologne), Magdalena Bogus(University Hospital Cologne), Matthew G. Soloway(University of North Carolina at Chapel Hill), Matthew D. Wilkerson(University of North Carolina at Chapel Hill), Yupeng Cun(University of Cologne), James McKay(Centre international de recherche sur le cancer), Denis Moro‐Sibilot(Inserm), Christian Brambilla(Inserm), Sylvie Lantuéjoul(Inserm), Nicolas Lemaître(Inserm), Alex Soltermann(University Hospital of Zurich), Walter Weder(University Hospital of Zurich), Verena Tischler(University Hospital of Zurich), Odd Terje Brustugun(Oslo University Hospital), Marius Lund‐Iversen(Oslo University Hospital), Åslaug Helland(University of Oslo), Steinar Solberg(Oslo University Hospital), Sascha Ansén(University Hospital Cologne), Gavin Wright(Peter MacCallum Cancer Centre), Benjamin Solomon(Peter MacCallum Cancer Centre), Luca Roz(Fondazione IRCCS Istituto Nazionale dei Tumori), Ugo Pastorino(Fondazione IRCCS Istituto Nazionale dei Tumori), Iver Petersen(Jena University Hospital), Joachim H. Clement(Jena University Hospital), Jörg Sänger(Zentralklinik Bad Berka), Jürgen Wolf(University Hospital Cologne), Martin Vingron(Max Planck Institute for Molecular Genetics), Thomas Zander(University Hospital Cologne), Sven Perner(Research Center Borstel - Leibniz Lung Center), William D. Travis(Memorial Sloan Kettering Cancer Center), Stefan A. Haas(Max Planck Institute for Molecular Genetics), Magali Olivier(Centre international de recherche sur le cancer), Matthieu Foll(Centre international de recherche sur le cancer), Reinhard Büttner(University Hospital Cologne), D. Neil Hayes(University of North Carolina at Chapel Hill), Élisabeth Brambilla(Inserm), Lynnette Fernandez‐Cuesta(University of Cologne), Roman K. Thomas(German Cancer Research Center)

Nature Communications

March 7, 2018

10.1038/s41467-018-03099-x

Cited by 370Open Access

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Abstract

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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