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ResearchIn-Press PreviewGeneticsOncology Open Access | 10.1172/JCI170217

Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer

Florian Malchers,1 Lucia Nogova,2 Martijn H. van Attekum,3 Lukas Maas,3 Johannes Brägelmann,3 Christoph Bartenhagen,4 Luc Girard,5 Graziella Bosco,3 Ilona Dahmen,3 Sebastian Michels,2 Clare E. Weeden,6 Andreas H. Scheel,7 Lydia Meder,2 Kristina Golfmann,2 Philipp Schuldt,2 Janna Siemanowski,7 Jan Rehker,7 Sabine Merkelbach-Bruse,7 Roopika Menon,8 Oliver Gautschi,9 Johannes M. Heuckmann,8 Elisabeth Brambilla,10 Marie-Liesse Asselin-Labat,6 Thorsten Persigehl,11 John D. Minna,5 Henning Walczak,12 Roland T. Ullrich,2 Matthias Fischer,4 Hans Christian Reinhardt,13 Juergen Wolf,2 Reinhard Büttner,7 Martin Peifer,3 Julie George,3 and Roman K. Thomas3

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Malchers, F. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Nogova, L. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by van Attekum, M. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Maas, L. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Brägelmann, J. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Bartenhagen, C. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Girard, L. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Bosco, G. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Dahmen, I. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Michels, S. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Weeden, C. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Scheel, A. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Meder, L. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Golfmann, K. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Schuldt, P. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Siemanowski, J. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Rehker, J. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Merkelbach-Bruse, S. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Menon, R. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Gautschi, O. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Heuckmann, J. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Brambilla, E. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Asselin-Labat, M. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Persigehl, T. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Minna, J. in: JCI | PubMed | Google Scholar |

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

Find articles by Walczak, H. in: JCI | PubMed | Google Scholar

1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

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1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

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1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

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1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

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1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

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1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

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1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

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1University of Cologne, Cologne, Germany

2Department I of Internal Medicine, Medical Center of the University of Cologne, Cologne, Germany

3Department of Translational Genomics, University of Cologne, Cologne, Germany

4Department of Pediatric and Adolescent Medicine, University Hospital Cologne, Cologne, Germany

5Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, United States of America

6Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

7Institute of Pathology, University of Cologne, Cologne, Germany

8DISCO Pharmaceuticals GmbH, DISCO Pharmaceuticals GmbH, Cologne, Germany

9Cancer Center, Lucerne Cantonal Hospital, Lucerne, Switzerland

10Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, Grenoble, France

11Department of Radiology, University Hospital of Cologne, Cologne, Germany

12Institute of Biochemistry I, University of Cologne, Cologne, Germany

13Department of Internal Medicine, University of Essen-Duisburg, Essen, Germany

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Published August 22, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI170217.
Copyright © 2023, Malchers et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 22, 2023 - Version history
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Abstract

The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer has fueled hopes that FGFR1, located inside this amplicon, might be a therapeutic target. In a clinical trial, only 11% of patients with 8p11 amplification (detected by FISH) responded to FGFR kinase inhibitor treatment. To understand the mechanism of FGFR1 dependency, we performed deep genomic characterization of 52 squamous cell lung carcinomas with 8p11-p12-amplification, including 10 tumors obtained from patients who had been treated with FGFR inhibitors. We discovered somatically altered variants of FGFR1 with deletion of exons 1-8 that resulted from intragenic tail-to-tail rearrangements. These ectodomain-deficient FGFR1 variants (ΔEC-FGFR1) were expressed in the affected tumors and tumorigenic in in-vitro and in-vivo. Mechanistically, Breakage-Fusion-Bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. However, only tumors with tail-to-tail rearrangements within or in close proximity upstream of FGFR1 exhibited FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven squamous cell lung cancer. Specifically, FGFR1 ectodomain deficient and FGFR1-centered amplifications caused by tail-to-tail rearrangements are novel somatic genomic event, which might be predictive of therapeutically relevant FGFR1 dependency.

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