Research ArticleCancer

A Genomics-Based Classification of Human Lung Tumors

Science Translational Medicine  30 Oct 2013:
Vol. 5, Issue 209, pp. 209ra153
DOI: 10.1126/scitranslmed.3006802

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Abstract

We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

Footnotes

  • Data analysis team: Danila Seidel,1,2* Thomas Zander,1,3,52* Lukas C. Heukamp,8,52* Martin Peifer,1* Marc Bos,3,52* Lynnette Fernández-Cuesta,1 Frauke Leenders,1,2 Xin Lu,1 Sascha Ansén,3 Masyar Gardizi,3,52 Chau Nguyen,5,11 Johannes Berg,5 Prudence Russell,46 Zoe Wainer,45 Hans-Ulrich Schildhaus,8,52,76 Toni-Maree Rogers,13 Benjamin Solomon,44 William Pao,38 Scott L. Carter,42 Gad Getz,42 D. Neil Hayes,51 Matthew D. Wilkerson,51,77 Erik Thunnissen,24 William D. Travis,26 Sven Perner,14 Gavin Wright,45,78 Elisabeth Brambilla,36,37 Reinhard Büttner,2,8,52 Jürgen Wolf,2,3,52 and Roman K. Thomas1,2,8,52

    Biospecimens core resources: Franziska Gabler,2,4 Ines Wilkening,4 Christian Müller,1 Ilona Dahmen,1 Roopika Menon,14 Katharina König,8,52 Kerstin Albus,8,52 Sabine Merkelbach-Bruse,8,52 Jana Fassunke,8,52 Katja Schmitz,8,52 Helen Kuenstlinger,8,52 Michaela A. Kleine,8,52 Elke Binot,8,52 Silvia Querings,2,4 Janine Altmüller,6,10 Ingelore Bäßmann,6 Peter Nürnberg,6,9,10 Peter M. Schneider,12 and Magdalena Bogus12

    Pathology committee: Reinhard Büttner,2,8 Sven Perner,14 Prudence Russell,46 Erik Thunnissen,24 William D. Travis,26 and Elisabeth Brambilla36,37

    Biospecimens and data source sites: Alex Soltermann,33 Holger Moch,33 Odd Terje Brustugun,31,32 Steinar Solberg,30 Marius Lund-Iversen,73 Åslaug Helland,31,32 Thomas Muley,18,48 Hans Hoffmann,18 Philipp A. Schnabel,17,48 Yuan Chen,15 Harry Groen,22 Wim Timens,23 Hannie Sietsma,23 Joachim H. Clement,71 Walter Weder,33 Jörg Sänger,19 Erich Stoelben,7 Corinna Ludwig,7 Walburga Engel-Riedel,7 Egbert Smit,24 Daniëlle A. M. Heideman,24 Peter J. F. Snijders,24 Lucia Nogova,3,52 Martin L. Sos,3,52,53 Christian Mattonet,3,52 Karin Töpelt,3,52 Matthias Scheffler,3,52 Eray Goekkurt,52,55 Rainer Kappes,52,56,62 Stefan Krüger,52,56 Kato Kambartel,52,57 Dirk Behringer,52,58 Wolfgang Schulte,52,59 Wolfgang Galetke,52,60 Winfried Randerath,52,61 Matthias Heldwein,52,63 Andreas Schlesinger,52,64 Monika Serke,52,65 Khosro Hekmat,52,63 Konrad F. Frank,52,66 Roland Schnell,52,67 Marcel Reiser,52,68 Ali-Nuri Hünerlitürkoglu,52,69 Stephan Schmitz,52,70 Lisa Meffert,52,40 Yon-Dschun Ko,52,40 Markus Litt-Lampe,52,72 Ulrich Gerigk,52,41 Rainer Fricke,54 Benjamin Besse,36 Christian Brambilla,37 Sylvie Lantuejoul,36,75 Philippe Lorimier,36 Denis Moro-Sibilot,37 Federico Cappuzzo,27 Claudia Ligorio,28 Stefania Damiani,28 John K. Field,29 Russell Hyde,29 Pierre Validire,35 Philippe Girard,35 Lucia A. Muscarella,47 Vito M. Fazio,47,74 Michael Hallek,2,3 Jean-Charles Soria,34 Scott L. Carter,42 Gad Getz,42 D. Neil Hayes,51 Matthew D. Wilkerson,51,77 Viktor Achter,50 and Ulrich Lang49,50

    Writing committee: Danila Seidel,1,2* Thomas Zander,1,3,52* Lukas C. Heukamp,8,52* Martin Peifer,1* Marc Bos,3,52* William Pao,38 William D. Travis,26 Elisabeth Brambilla,36,37 Reinhard Büttner,2,8,52 Jürgen Wolf,2,3,52 and Roman K Thomas1,2,8,52

    *These authors contributed equally to this work.

    Study leaders: Reinhard Büttner,2,8,52 Jürgen Wolf,2,3,52 and Roman K. Thomas1,2,8,52

    1Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University of Cologne, 50931 Cologne, Germany.

    2Laboratory of Translational Cancer Genomics, Center of Integrated Oncology Köln-Bonn, University of Cologne, 50937 Cologne, Germany.

    3Department I of Internal Medicine, Center of Integrated Oncology Köln-Bonn, University of Cologne, 50937 Cologne, Germany.

    4Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne, 50931 Cologne, Germany.

    5Institute for Theoretical Physics, University of Cologne, 50937 Cologne, Germany.

    6Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.

    7Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln gGmbH, 51109 Cologne, Germany.

    8Institute of Pathology, Center of Integrated Oncology Köln-Bonn, University of Cologne, 50937 Cologne, Germany.

    9Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

    10Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.

    11Bonn-Cologne Graduate School of Physics and Astronomy, 53115 Bonn, Germany.

    12Institute of Legal Medicine, University of Cologne, 50823 Cologne, Germany.

    13Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, 3002 Victoria, Australia.

    14Department of Prostate Cancer Research at the Institute of Pathology, University Hospital of Bonn, 53127 Bonn, Germany.

    15Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany.

    16Technical University Dortmund, Department of Chemical Biology, 44227 Dortmund, Germany.

    17Institute of Pathology, University of Heidelberg, 69120 Heidelberg, Germany.

    18Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, 69126 Heidelberg, Germany.

    19Institute for Pathology Bad Berka, 99438 Bad Berka, Germany.

    20Department for Internal Medicine II, Jena University Hospital, Friedrich-Schiller University, 07740 Jena, Germany.

    21Center for Medical Genetics, Ghent University, 9000 Ghent, Belgium.

    22Department of Pulmonary Diseases, University of Groningen, University Medical Centre Groningen, 9713 GZ Groningen, the Netherlands.

    23Department Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.

    24Department of Pathology, VU University Medical Center Amsterdam, 1007 MB Amsterdam, the Netherlands.

    25Department of Pulmonary Diseases, VU University Medical Center Amsterdam, 1007 MB Amsterdam, the Netherlands.

    26Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

    27Department of Medical Oncology, Ospedale Civile, 57100 Livorno, Italy.

    28Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy.

    29Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, University of Liverpool Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool L3 9TA, UK.

    30Department of Thoracic Surgery, Rikshospitalet, Oslo University Hospital, N-0027 Oslo, Norway.

    31Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0424 Oslo, Norway.

    32Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway.

    33Institute for Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.

    34Phase I Unit–Department of Medicine, Institute Gustave Roussy, 94800 Villejuif, France.

    35France Service d’Anatomie-Pathologie, Institut Mutualiste Montsouris, 75014 Paris, France.

    36Department Cancer Medicine, Institute Gustave Roussy, 94800 Villejuif, France.

    37Pole de Cancérologie et Médecine Aigue Communautaire, CHU Grenoble, CS 10217, 38043 Grenoble, France and INSERM U823, Grenoble, France.

    38Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.

    39Department of Genome Sciences, University of Washington, Seattle, WA 98195–5065, USA.

    40Klinik für Internistische Onkologie Evangelische Kliniken Bonn, 53113 Bonn, Germany.

    41Klinik für Thoraxchirurgie, Malteser Krankenhaus, 53123 Bonn, Germany.

    42The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

    43Department of Genetics, Stanford University, Stanford, CA, USA.

    44Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, 3002 Victoria, Australia.

    45The University of Melbourne Department of Surgery, St Vincent’s Hospital, Melbourne, 3065 Victoria, Australia.

    46Department of Pathology, St. Vincent’s Hospital, Melbourne, 3065 Victoria, Australia.

    47Laboratory of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

    48Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany.

    49Department of Informatics, University of Cologne, 50931 Cologne, Germany.

    50Computing Center, University of Cologne, 50931 Cologne, Germany.

    51Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

    52Network Genomic Medicine, University Hospital Cologne, Center of Integrated Oncology Köln Bonn, 50937 Cologne, Germany.

    53Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.

    54Epidemiologisches Krebsregister NRW gGmbH, 48149 Münster, Germany.

    55Hämatologisch-Onkologische Praxis Eppendorf, 20249 Hamburg, Germany.

    56Klinik für Pneumologie, Florence Nightingale Krankenhaus, 40489 Düsseldorf, Germany.

    57Lungenklinik, Krankenhaus Bethanien Moers, 47441 Moers, Germany.

    58Klinik für Hämatologie, Onkologie und Palliativmedizin, Augusta Kliniken Bochum, 44791 Bochum, Lungenkrebszentrum Herne-Bochum, Germany.

    59Abteilung für Pneumologie, Malteser Krankenhaus, 53123 Bonn, Germany.

    60Klinik für Innere Medizin, Krankenhaus der Augustinerinnen, 50678 Köln, Germany.

    61Klinik für Pneumologie, Krankenhaus Bethanien Solingen, 42669 Solingen, Germany.

    62Schwerpunktpraxis für Lungen- und Bronchialheilkunde, Allergologie, Friedrichstr. 33-35, 40217 Düsseldorf, Germany.

    63Department of Cardiothoracic Surgery, University Hospital Cologne, Center of Integrated Oncology Köln Bonn, 50924 Cologne, Germany.

    64Abteilung für Pneumologie, Evangelisches Krankenhaus Kalk, 51103 Köln, Germany.

    65Abteilung Pneumologie III/Thorakale Onkologie, Lungenklinik Hemer, 58675 Hemer, Germany.

    66Department III of Internal Medicine, University Hospital Cologne, Center of Integrated Oncology Köln Bonn, 50924 Cologne, Germany.

    67PIOH Frechen, Kölner Straße 9, 50226 Frechen, Germany.

    68PIOH Köln, Richard Wagner Straße 13-17, 50674 Köln, Germany.

    69Lukaskrankenhaus Neuss, Innere Medizin II, 41464 Neuss, Germany.

    70Gemeinschaftspraxis für Hämatologie und Onkologie, Sachsenring 69, 50677 Köln, Germany.

    71Department Hematology and Oncology, Jena University Hospital, Friedrich-Schiller University, 07747 Jena, Germany.

    72Innere Medizin II Gastroenterologie/Pneumologie/Onkologie, Marienhospital Brühl, 50321 Brühl, Germany.

    73Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway.

    74University Campus Bio-Medico of Roma, Center for Integrated Research, Laboratory for Molecular Medicine and Biotechnology, 00128 Rome, Italy.

    75Université Joseph Fourier-INSERM U 823 Institut Albert Bonniot, 38700 La Tronche, France.

    76Institute of Pathology, University Hospital Goettingen, Goettingen, Germany.

    77Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

    78Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, 3002 Victoria, Australia.

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