A Genomics-Based Classification of Human Lung Tumors

Sci Transl Med 30 October 2013:
Vol. 5, Issue 209, p. 209ra153
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3006802

Research Article

CANCER

A Genomics-Based Classification of Human Lung Tumors

The Clinical Lung Cancer Genome Project (CLCGP) and Network Genomic Medicine (NGM),*,†

↵†Corresponding authors. E-mail: roman.thomas@uni-koeln.de (R.T.); reinhard.buettner@uk-koeln.de (R.B.); juergen.wolf@uk-koeln.de (J.W.)

↵* Lists of participants and their affiliations appear at the end of the paper.

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.

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. Thomas^1,2,8,52
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 Brambilla^36,37
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 Lang^49,50
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 Thomas^1,2,8,52
*These authors contributed equally to this work.
Study leaders: Reinhard Büttner,^2,8,52 Jürgen Wolf,^2,3,52 and Roman K. Thomas^1,2,8,52
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.

Citation: T. C. L. C. G. P. (. a. N. G. M. (NGM), A Genomics-Based Classification of Human Lung Tumors. Sci. Transl. Med. 5, 209ra153 (2013).

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