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; Noemie Leblay; Graham Byrnes; Ruping Sun; Aurélien De Reynies; 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 D McKay; Denis Moro-Sibilot; Christian G Brambilla; Sylvie Lantuejoul; Nicolas Lemaitre; 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; David Neil Hayes; Elisabeth 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

Nat Commun. 2018 Mar 13;9(1):1048. doi: 10.1038/s41467-018-03099-x.

Authors

Julie George¹, Vonn Walter^{2

3}, Martin Peifer^{4

5}, Ludmil B Alexandrov⁶, Danila Seidel⁴, Frauke Leenders⁴, Lukas Maas⁴, Christian Müller⁴, Ilona Dahmen⁴, Tiffany M Delhomme⁷, Maude Ardin⁸, Noemie Leblay⁷, Graham Byrnes⁹, Ruping Sun¹⁰, Aurélien De Reynies¹¹, Anne McLeer-Florin¹², Graziella Bosco⁴, Florian Malchers⁴, Roopika Menon¹³, Janine Altmüller^{5

14

15}, Christian Becker¹⁴, Peter Nürnberg^{5

14

16}, Viktor Achter¹⁷, Ulrich Lang^{17

18}, Peter M Schneider¹⁹, Magdalena Bogus¹⁹, Matthew G Soloway², Matthew D Wilkerson²⁰, Yupeng Cun^{4

5}, James D McKay⁷, Denis Moro-Sibilot²¹, Christian G Brambilla²¹, Sylvie Lantuejoul^{22

23}, Nicolas Lemaitre²², Alex Soltermann²⁴, Walter Weder²⁵, Verena Tischler²⁴, Odd Terje Brustugun^{26

27}, Marius Lund-Iversen²⁸, Åslaug Helland^{25

26}, Steinar Solberg²⁹, Sascha Ansén³⁰, Gavin Wright³¹, Benjamin Solomon³², Luca Roz³³, Ugo Pastorino³⁴, Iver Petersen³⁵, Joachim H Clement³⁶, Jörg Sänger³⁷, Jürgen Wolf³⁰, Martin Vingron¹⁰, Thomas Zander^{38

39}, Sven Perner⁴⁰, William D Travis⁴¹, Stefan A Haas¹⁰, Magali Olivier⁸, Matthieu Foll⁷, Reinhard Büttner³⁹, David Neil Hayes², Elisabeth Brambilla⁴², Lynnette Fernandez-Cuesta^{4

7}, Roman K Thomas^{43

44

45}

Affiliations

¹ Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany. jgeorge@uni-koeln.de.
² UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7295, USA.
³ Department of Biochemistry and Molecular Biology, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033, USA.
⁴ Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.
⁵ Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
⁶ Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, La Jolla, San Diego, CA, 92093, USA.
⁷ Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer (IARC-WHO), Lyon, 69008, France.
⁸ Molecular Mechanisms and Biomarkers Group, Section of Mechanisms of Carcinogenesis, International Agency for Research on Cancer (IARC-WHO), 69008, Lyon, France.
⁹ Section of Environment and Radiation, International Agency for Research on Cancer (IARC-WHO), 69008, Lyon, France.
¹⁰ Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany.
¹¹ Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, 14 rue Corvisart, Paris, 75013, France.
¹² CHU Grenoble Alpes, UGA/INSERM U1209/CNRS, Grenoble, France.
¹³ NEO New Oncology GmbH, 51105, Cologne, Germany.
¹⁴ Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany.
¹⁵ Institute of Human Genetics, University Hospital Cologne, 50931, Cologne, Germany.
¹⁶ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
¹⁷ Computing Center, University of Cologne, 50931, Cologne, Germany.
¹⁸ Department of Informatics, University of Cologne, 50931, Cologne, Germany.
¹⁹ Institute of Legal Medicine, University Hospital Cologne, 50823, Cologne, Germany.
²⁰ Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, NC, 27599-7295, USA.
²¹ CHUGA Grenoble, INSERM U 1209, University Grenoble Alpes, Institute of Advanced Biosciences (IAB), 38043, CS10217, Grenoble, France.
²² Department of Pathology, CHUGA, INSERM U 1209, University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043, CS10217, Grenoble, France.
²³ Department of Biopathology, Centre Léon Bérard UNICANCER, 69008, Lyon, France.
²⁴ Institute of Pathology and Molecular Pathology, University Hospital Zurich, 8091, Zurich, Switzerland.
²⁵ Department of Thoracic Surgery, University Hospital Zurich, 8091, Zurich, Switzerland.
²⁶ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0424, Oslo, Norway.
²⁷ Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway.
²⁸ Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway.
²⁹ Department of Thoracic Surgery, Rikshospitalet, Oslo University Hospital, N-0027, Oslo, Norway.
³⁰ Department of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937, Cologne, Germany.
³¹ Department of Surgery, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065, Melbourne, Victoria, Australia.
³² Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, 3065, Melbourne, Victoria, Australia.
³³ Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS-Istituto Nazionale Tumori, Via Venezian 1, 20133, Milan, Italy.
³⁴ Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, 20133, Milan, Italy.
³⁵ Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743, Jena, Germany.
³⁶ Department of Internal Medicine II, Jena University Hospital, Friedrich-Schiller-University, 07743, Jena, Germany.
³⁷ Institute for Pathology Bad Berka, 99438, Bad Berka, Germany.
³⁸ Gastrointestinal Cancer Group Cologne, Center of Integrated Oncology Cologne-Bonn, Department I for Internal Medicine, University Hospital of Cologne, 50823, Cologne, Germany.
³⁹ Department of Pathology, University Hospital Cologne, 50937, Cologne, Germany.
⁴⁰ Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, 23538 Luebeck and 23845 Borstel, Borstel, Germany.
⁴¹ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
⁴² Department of Pathology, CHUGA, INSERM U 1209, University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043, CS10217, Grenoble, France. EBrambilla@chu-grenoble.fr.
⁴³ Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany. roman.thomas@uni-koeln.de.
⁴⁴ Department of Pathology, University Hospital Cologne, 50937, Cologne, Germany. roman.thomas@uni-koeln.de.
⁴⁵ German Cancer Research Center, German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. roman.thomas@uni-koeln.de.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Publication types

MeSH terms

Grants and funding