title: Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids.
abstract: Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids.
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Lynnette
authors.initials: L
authors.lastname: Fernandez-Cuesta
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, D-14195 Berlin, Germany.
authors.forename: Ruping
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Pathology, University Hospital Medical Center, University of Cologne, 50937 Cologne, Germany.
authors.forename: Luka
authors.initials: L
authors.lastname: Ozretić
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.|Laboratory of Translational Cancer Genomics, Center of Integrated Oncology Cologne - Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Danila
authors.initials: D
authors.lastname: Seidal
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.|Department I of Internal Medicine, Center of Integrated Oncology Kö ln-Bonn, University of Cologne, 50924 Cologne, Germany.|Network Genomic Medicine, University Hospital Cologne, Center of Integrated Oncology Cologne Bonn, 50924 Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zander
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.|Laboratory of Translational Cancer Genomics, Center of Integrated Oncology Cologne - Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Leenders
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: George
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Dahmen
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Berit
authors.initials: B
authors.lastname: Pinther
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Graziella
authors.initials: G
authors.lastname: Bosco
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, 50931 Germany.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Konrad
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, 50931 Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne 50931, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Cologne Center for Genomics (CCG), University of Cologne, Cologne, 50931 Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Computing Center, University of Cologne, 50931 Cologne, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Achter
authors.affiliation: Computing Center, University of Cologne, 50931 Cologne, Germany.|Department of Informatics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lang
authors.affiliation: Institute of Legal Medicine, University of Cologne, 50823 Cologne, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schneider
authors.affiliation: Institute of Legal Medicine, University of Cologne, 50823 Cologne, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bogus
authors.affiliation: Institute for Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Alex
authors.initials: A
authors.lastname: Soltermann
authors.affiliation: Institute of clinical medicine, Faculty of Medicine, University of Oslo, N-0424 Oslo, Norway.|Department of oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway.
authors.forename: Odd Terje
authors.initials: OT
authors.lastname: Brustugun
authors.affiliation: Institute of clinical medicine, Faculty of Medicine, University of Oslo, N-0424 Oslo, Norway.|Department of oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway.
authors.forename: Åslaug
authors.initials: Å
authors.lastname: Helland
authors.affiliation: Department of Thoracic Surgery, Rikshospitalet, Oslo University Hospital, N-0027 Oslo, Norway.
authors.forename: Steinar
authors.initials: S
authors.lastname: Solberg
authors.affiliation: Department of pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway.
authors.forename: Marius
authors.initials: M
authors.lastname: Lund-Iversen
authors.affiliation: Department I of Internal Medicine, Center of Integrated Oncology Kö ln-Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Ansén
authors.affiliation: Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln gGmbH, 51109 Cologne, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Stoelben
authors.affiliation: University of Melbourne Department of Surgery, St Vincent's Hospital, Melbourne, 3065 Victoria, Australia.
authors.forename: Gavin M
authors.initials: GM
authors.lastname: Wright
authors.affiliation: Department of Pathology, St. Vincent's Hospital, Melbourne, 3065 Victoria, Australia.
authors.forename: Prudence
authors.initials: P
authors.lastname: Russell
authors.affiliation: University of Melbourne Department of Surgery, St Vincent's Hospital, Melbourne, 3065 Victoria, Australia.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Wainer
authors.affiliation: Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, 3002 Victoria, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Solomon
authors.affiliation: Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool Cancer Research Centre, Liverpool, L3 9TA, UK.
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.affiliation: Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool Cancer Research Centre, Liverpool, L3 9TA, UK.
authors.forename: Russell
authors.initials: R
authors.lastname: Hyde
authors.affiliation: Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool Cancer Research Centre, Liverpool, L3 9TA, UK.
authors.forename: Michael Pa
authors.initials: MP
authors.lastname: Davies
authors.affiliation: Department of Pathology, University Hospital Medical Center, University of Cologne, 50937 Cologne, Germany.|Network Genomic Medicine, University Hospital Cologne, Center of Integrated Oncology Cologne Bonn, 50924 Cologne, Germany.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.affiliation: Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany.
authors.forename: Iver
authors.initials: I
authors.lastname: Petersen
authors.affiliation: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, 53127 Bonn, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN37232, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Lovly
authors.affiliation: Department of Medical Oncology, Istituto Toscano Tumouri, 57100 Livorno, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Travis
authors.affiliation: Laboratory of Translational Cancer Genomics, Center of Integrated Oncology Cologne - Bonn, University of Cologne, 50924 Cologne, Germany.|Department I of Internal Medicine, Center of Integrated Oncology Kö ln-Bonn, University of Cologne, 50924 Cologne, Germany.|Network Genomic Medicine, University Hospital Cologne, Center of Integrated Oncology Cologne Bonn, 50924 Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, D-14195 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Vingron
authors.affiliation: Department of Pathology, CHU Grenoble INSERM U823, Institute Albert Bonniot 38043 CS10217 Grenoble, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, D-14195 Berlin, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Haas
authors.affiliation: Department of Pathology, University Hospital Medical Center, University of Cologne, 50937 Cologne, Germany.|Laboratory of Translational Cancer Genomics, Center of Integrated Oncology Cologne - Bonn, University of Cologne, 50924 Cologne, Germany.|Network Genomic Medicine, University Hospital Cologne, Center of Integrated Oncology Cologne Bonn, 50924 Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50924 Cologne, Germany.|Department of Pathology, University Hospital Medical Center, University of Cologne, 50937 Cologne, Germany.|Laboratory of Translational Cancer Genomics, Center of Integrated Oncology Cologne - Bonn, University of Cologne, 50924 Cologne, Germany.
authors.forename: Roman K
authors.initials: RK
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002276:Carcinoid Tumor / Q000235:genetics* / Q000473:pathology; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D002874:Chromosome Mapping; D056915:DNA Copy Number Variations; D059472:Exome / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult