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

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

Author information

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 ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, 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.

PMID:
29535388
PMCID:
PMC5849599
DOI:
10.1038/s41467-018-03099-x
[Indexed for MEDLINE]
Free PMC Article

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