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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.
Afiliação
  • George J; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany. jgeorge@uni-koeln.de.
  • Walter V; UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7295, USA.
  • Peifer M; Department of Biochemistry and Molecular Biology, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033, USA.
  • Alexandrov LB; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.
  • Seidel D; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
  • Leenders F; Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, La Jolla, San Diego, CA, 92093, USA.
  • Maas L; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.
  • Müller C; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.
  • Dahmen I; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.
  • Delhomme TM; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.
  • Ardin M; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.
  • Leblay N; Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer (IARC-WHO), Lyon, 69008, France.
  • Byrnes G; Molecular Mechanisms and Biomarkers Group, Section of Mechanisms of Carcinogenesis, International Agency for Research on Cancer (IARC-WHO), 69008, Lyon, France.
  • Sun R; Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer (IARC-WHO), Lyon, 69008, France.
  • De Reynies A; Section of Environment and Radiation, International Agency for Research on Cancer (IARC-WHO), 69008, Lyon, France.
  • McLeer-Florin A; Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany.
  • Bosco G; Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, 14 rue Corvisart, Paris, 75013, France.
  • Malchers F; CHU Grenoble Alpes, UGA/INSERM U1209/CNRS, Grenoble, France.
  • Menon R; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.
  • Altmüller J; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.
  • Becker C; NEO New Oncology GmbH, 51105, Cologne, Germany.
  • Nürnberg P; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
  • Achter V; Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany.
  • Lang U; Institute of Human Genetics, University Hospital Cologne, 50931, Cologne, Germany.
  • Schneider PM; Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany.
  • Bogus M; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
  • Soloway MG; Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany.
  • Wilkerson MD; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
  • Cun Y; Computing Center, University of Cologne, 50931, Cologne, Germany.
  • McKay JD; Computing Center, University of Cologne, 50931, Cologne, Germany.
  • Moro-Sibilot D; Department of Informatics, University of Cologne, 50931, Cologne, Germany.
  • Brambilla CG; Institute of Legal Medicine, University Hospital Cologne, 50823, Cologne, Germany.
  • Lantuejoul S; Institute of Legal Medicine, University Hospital Cologne, 50823, Cologne, Germany.
  • Lemaitre N; UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7295, USA.
  • Soltermann A; Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, NC, 27599-7295, USA.
  • Weder W; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, 50931, Germany.
  • Tischler V; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
  • Brustugun OT; Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer (IARC-WHO), Lyon, 69008, France.
  • Lund-Iversen M; CHUGA Grenoble, INSERM U 1209, University Grenoble Alpes, Institute of Advanced Biosciences (IAB), 38043, CS10217, Grenoble, France.
  • Helland Å; CHUGA Grenoble, INSERM U 1209, University Grenoble Alpes, Institute of Advanced Biosciences (IAB), 38043, CS10217, Grenoble, France.
  • Solberg S; Department of Pathology, CHUGA, INSERM U 1209, University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043, CS10217, Grenoble, France.
  • Ansén S; Department of Biopathology, Centre Léon Bérard UNICANCER, 69008, Lyon, France.
  • Wright G; Department of Pathology, CHUGA, INSERM U 1209, University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043, CS10217, Grenoble, France.
  • Solomon B; Institute of Pathology and Molecular Pathology, University Hospital Zurich, 8091, Zurich, Switzerland.
  • Roz L; Department of Thoracic Surgery, University Hospital Zurich, 8091, Zurich, Switzerland.
  • Pastorino U; Institute of Pathology and Molecular Pathology, University Hospital Zurich, 8091, Zurich, Switzerland.
  • Petersen I; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0424, Oslo, Norway.
  • Clement JH; Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway.
  • Sänger J; Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway.
  • Wolf J; Department of Thoracic Surgery, University Hospital Zurich, 8091, Zurich, Switzerland.
Nat Commun ; 9(1): 1048, 2018 03 13.
Article em En | MEDLINE | ID: mdl-29535388
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tumores Neuroendócrinos / Carcinoma Neuroendócrino / Carcinoma Pulmonar de Células não Pequenas / Carcinoma de Pequenas Células do Pulmão Limite: Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Alemanha
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tumores Neuroendócrinos / Carcinoma Neuroendócrino / Carcinoma Pulmonar de Células não Pequenas / Carcinoma de Pequenas Células do Pulmão Limite: Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Alemanha