Letter | Published:

Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

Nature Genetics volume 44, pages 11041110 (2012) | Download Citation

Abstract

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis1,2,3. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 ± 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice4. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.

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Acknowledgements

We are indebted to the individuals donating their tumor specimens as part of the Clinical Lung Cancer Genome Project initiative. Additional biospecimens for this study were obtained from the Victorian Cancer Biobank (Melbourne, Australia). The Institutional Review Board (IRB) of each participating institution approved collection and use of all specimens in this study. We also thank our colleagues at The Cancer Genome Atlas Research Network (TCGA) and A.L. Kung for invaluable discussion and many helpful comments. This work was supported by the German Ministry of Science and Education (BMBF) as part of the NGFNplus program (grant 01GS08100 to R.K.T. and 01GS08101 to J.W. and P.N.), by the Max Planck Society (M.I.F.A.NEUR8061 to R.K.T.), by the Deutsche Forschungsgemeinschaft (DFG) through SFB832 (TP6 to R.K.T. and TP5 and Z1 to L.C.H. and R.B.) and TH1386/3-1 (to R.K.T. and M.L.S.), by the European Union's Framework Programme CURELUNG (HEALTH-F2-2010-258677 to R.K.T., J.F., E.B., C. Brambilla, S.L., B.B. and J.W.), by Stand Up To Cancer–American Association for Cancer Research Innovative Research Grant (SU2C-AACR-IR60109 to R.K.T. and W.P.), by the Behrens-Weise Foundation (to R.K.T.) and by an anonymous foundation to R.K.T. M.L.S. is a fellow of the International Association for the Study of Lung Cancer (IASLC). P.K.B. and L.H.K. thank the St. Jude Cell and Tissue Imaging facility and acknowledge support from the US National Institutes of Health (NIH) Cancer Center (grant P30 CA021765) and the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital. F.C. was supported by Associazione Italiana Ricerca sul Cancro (AIRC, grant IG 9425).

Author information

Author notes

    • Martin Peifer
    •  & Lynnette Fernández-Cuesta

    These authors contributed equally to this work.

Affiliations

  1. Department of Translational Genomics, University of Cologne, Cologne, Germany.

    • Martin Peifer
    • , Lynnette Fernández-Cuesta
    • , Martin L Sos
    • , Julie George
    • , Danila Seidel
    • , Dennis Plenker
    • , Frauke Leenders
    • , Thomas Zander
    • , Mirjam Koker
    • , Ilona Dahmen
    • , Christian Müller
    • , Johannes M Heuckmann
    • , Xin Lu
    •  & Roman K Thomas
  2. Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne, Cologne, Germany.

    • Martin Peifer
    • , Lynnette Fernández-Cuesta
    • , Martin L Sos
    • , Julie George
    • , Danila Seidel
    • , Dennis Plenker
    • , Frauke Leenders
    • , Thomas Zander
    • , Mirjam Koker
    • , Ilona Dahmen
    • , Christian Müller
    • , Franziska Gabler
    • , Ines Wilkening
    • , Stefanie Heynck
    • , Johannes M Heuckmann
    • , Xin Lu
    •  & Roman K Thomas
  3. Department I of Internal Medicine, University of Cologne, Cologne, Germany.

    • Martin L Sos
    • , Thomas Zander
    • , Sascha Ansén
    • , Michael Hallek
    • , Jürgen Wolf
    •  & Roman K Thomas
  4. Center of Integrated Oncology Köln–Bonn, University of Cologne, Cologne, Germany.

    • Martin L Sos
    • , Thomas Zander
    • , Sascha Ansén
    • , Michael Hallek
    • , Jürgen Wolf
    •  & Roman K Thomas
  5. Laboratory of Translational Cancer Genomics, Center of Integrated Oncology Kölm–Bonn, University of Cologne, Cologne, Germany.

    • Danila Seidel
    • , Frauke Leenders
    • , Michael Hallek
    • , Reinhard Büttner
    • , Jürgen Wolf
    •  & Roman K Thomas
  6. Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Lawryn H Kasper
    •  & Paul K Brindle
  7. Max Planck Institute for Molecular Genetics, Berlin, Germany.

    • Ruping Sun
    •  & Stefan Haas
  8. Institute of Prostate Cancer Research at the Institute of Pathology, University Hospital of Bonn, Bonn, Germany.

    • Roopika Menon
    • , Diana Böhm
    •  & Sven Perner
  9. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.

    • Vincenzo Di Cerbo
    •  & Robert Schneider
  10. Department of Pathology, University of Cologne, Cologne, Germany.

    • Hans-Ulrich Schildhaus
    • , Reinhard Büttner
    • , Lukas C Heukamp
    •  & Roman K Thomas
  11. Cologne Center for Genomics, University of Cologne, Cologne, Germany.

    • Janine Altmüller
    • , Ingelore Baessmann
    • , Christian Becker
    •  & Peter Nürnberg
  12. Center for Medical Genetics, Ghent University, Ghent, Belgium.

    • Bram de Wilde
    •  & Jo Vandesompele
  13. The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Scott L Carter
    • , Kristian Cibulskis
    • , Shantanu Banerji
    • , Gad Getz
    •  & Matthew Meyerson
  14. Department of Pediatrics, Stanford University, Stanford, California, USA.

    • Kwon-Sik Park
    •  & Julien Sage
  15. Department of Genetics, Stanford University, Stanford, California, USA.

    • Kwon-Sik Park
    •  & Julien Sage
  16. Department of Chemical Biology, Technical University Dortmund, Dortmund, Germany.

    • Daniel Rauh
    •  & Christian Grütter
  17. Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Cologne, Germany.

    • Matthias Fischer
  18. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.

    • Matthias Fischer
    •  & Peter Nürnberg
  19. Institute for Cancer Genetics, Columbia University, New York, New York, USA.

    • Laura Pasqualucci
  20. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.

    • Laura Pasqualucci
  21. Department of Surgery, St. Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.

    • Gavin Wright
    •  & Zoe Wainer
  22. Department of Pathology, St. Vincent's Hospital, Melbourne, Victoria, Australia.

    • Prudence Russell
  23. Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.

    • Iver Petersen
    •  & Yuan Chen
  24. Department of Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln, Cologne, Germany.

    • Erich Stoelben
    • , Corinna Ludwig
    •  & Walburga Engel-Riedel
  25. Instituteof Pathology, Heidelberg, Germany.

    • Philipp Schnabel
  26. Department of Thoracic Surgery, Thoraxklinik-Heidelberg, Heidelberg, Germany.

    • Hans Hoffmann
    •  & Thomas Muley
  27. Department of Pathology, Hospital Merheim, Kliniken der Stadt Köln, Cologne, Germany.

    • Michael Brockmann
  28. Laboratory of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

    • Lucia A Muscarella
    •  & Vito M Fazio
  29. Department of Pulmonary Diseases, University Medical Centre Groningen, Groningen, The Netherlands.

    • Harry Groen
  30. Department of Pathology, University Medical Centre Groningen, Groningen, The Netherlands.

    • Wim Timens
    •  & Hannie Sietsma
  31. Department of Pathology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.

    • Erik Thunnissen
    • , Daniëlle A M Heideman
    •  & Peter J F Snijders
  32. Department of Pulmonary Diseases, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.

    • Egbert Smit
  33. Department of Medical Oncology, Ospedale Civile, Livorno, Italy.

    • Federico Cappuzzo
  34. Department of Haematology and Oncologic Science, University Hospital Bologna, Bologna, Italy.

    • Claudia Ligorio
    •  & Stefania Damiani
  35. Roy Castle Lung Cancer Research Programme, The University of Liverpool Cancer Research Centre, University of Liverpool, Liverpool, UK.

    • John Field
  36. Department of Thoracic Surgery, Rikshospitalet, Oslo University Hospital, Oslo, Norway.

    • Steinar Solberg
  37. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

    • Odd Terje Brustugun
  38. Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

    • Odd Terje Brustugun
  39. Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

    • Marius Lund-Iversen
  40. Institute for Pathology Bad Berka, Bad Berka, Germany.

    • Jörg Sänger
  41. Department of Internal Medicine II, Jena University Hospital, Friedrich-Schiller University, Jena, Germany.

    • Joachim H Clement
  42. Institute for Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.

    • Alex Soltermann
    •  & Holger Moch
  43. Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.

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

    • Benjamin Solomon
  45. Phase I Unit–Department of Medicine, Institute Gustave Roussy, Villejuif, France.

    • Jean-Charles Soria
    •  & Benjamin Besse
  46. France Service d'Anatomie-Pathologie, Institut Mutualiste Montsouris, Paris, France.

    • Pierre Validire
  47. Department of Pathology, Université Joseph Fourier, Grenoble, France.

    • Elisabeth Brambilla
    • , Christian Brambilla
    • , Sylvie Lantuejoul
    •  & Philippe Lorimier
  48. Institut Albert Bonniot, Institute National de la Santé et de la Recherche Médicale (INSERM) U823, Université Joseph Fourier, Grenoble, France.

    • Elisabeth Brambilla
    • , Christian Brambilla
    •  & Sylvie Lantuejoul
  49. Institute of Legal Medicine, University of Cologne, Cologne, Germany.

    • Peter M Schneider
  50. Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.

    • William Pao
  51. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.

    • Matthew Meyerson
  52. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Matthew Meyerson
  53. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Matthew Meyerson
  54. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

    • Jay Shendure
  55. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7104, INSERM U964, Université de Strasbourg, Illkirch, France.

    • Matthew Meyerson
    •  & Robert Schneider
  56. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

    • Peter Nürnberg

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Contributions

M.P., L.F.-C., M.L.S., J.G., D.S., L.H.K., F.L.,T.Z., R.M., J.V., P.S., J. Sage, R. Schneider, R.B., S.P., L.C.H., P.K.B. and R.K.T. conceived and designed the experiments. L.F.-C., M.L.S., J.G., D.S., L.H.K., D.P., R.M., M.K., I.D., C.M., V.D.C., H.-U.S., J.A., I.B., C. Becker, B.d.W., D.B., F.G., I.W., S. Heynck, J.M.H. and P.M.S. performed experiments. M.P., L.F.-C., M.L.S., J.G., D.S., L.H.K., D.P., F.L., R. Sun, T.Z., R.M., V.D.C., B.d.W., J.V., X.L., W.P., M.M., J. Sage, R. Schneider, S.P., L.C.H., P.K.B., S. Haas and R.K.T. analyzed the data. M.P., R. Sun, S.A., S.L.C., K.C., S.B., G.G., K.-S.P., D.R., C.G., M.F., L.P., G.W., Z.W., P.R., I.P., Y.C., E. Stoelben, C. Ludwig, P.S., H.H., T.M., M.B., W.E.-R., L.A.M., V.M.F., H.G., W.T., H.S., E.T., E. Smit, D.A.M.H., P.J.F.S., F.C., C. Ligorio, S.D., J.F., S.S., O.T.B., M.L.-I., J. Sänger, J.H.C., A.S., H.M., W.W., B.S., J.-C.S., P.V., B.B., E.B., C. Brambilla, S.L., P.L., M.H., J. Sage, J. Shendure, R. Schneider, R.B., S.P., L.C.H., J.W., P.N., L.C.H., P.K.B. and S. Haas contributed reagents, materials or analysis tools. M.P., L.F.-C. and R.K.T. wrote the manuscript.

Competing interests

R.K.T. reports the following potential sources of conflict of interest: consulting and lecture fees (Sanofi-Aventis, Merck, Bayer, Eli Lilly, Roche, Boehringer Ingelheim, Johnson & Johnson, AstraZeneca, Atlas-Biolabs and Daiichi-Sankyo) and research support (AstraZeneca, Merck and EOS). R.K.T. is a founder and shareholder of Blackfield, a company involved in cancer genome analysis services and cancer genomics–based drug discovery. M.P. and J.M.H. are shareholders of Blackfield. J.M.H. is a full-time employee of Blackfield.

Corresponding author

Correspondence to Roman K Thomas.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note and Supplementary Figures 1–12

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    Supplementary Tables

    Supplementary Tables 1–13

About this article

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DOI

https://doi.org/10.1038/ng.2396

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