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

Autor: Malchers F; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany., Nogova L; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany., van Attekum MH; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany., Maas L; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany., Brägelmann J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany.; Mildred Scheel School of Oncology, Cologne, University Hospital Cologne, Medical Faculty, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany., Bartenhagen C; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, University Hospital Cologne, Medical Faculty, Cologne, Germany., Girard L; University of Texas Southwestern Medical Center, Dallas, Texas, USA., Bosco G; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany., Dahmen I; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany., Michels S; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany., Weeden CE; Personalized Oncology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Parkville, Australia., Scheel AH; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany., Meder L; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany., Golfmann K; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany., Schuldt P; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany., Siemanowski J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany., Rehker J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany., Merkelbach-Bruse S; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany., Menon R; DISCO Pharmaceuticals GmbH, Cologne, Germany., Gautschi O; University of Berne and Cantonal Hospital of Lucerne, Cantonal Hospital of Lucerne, Lucerne, Switzerland., Heuckmann JM; DISCO Pharmaceuticals GmbH, Cologne, Germany., Brambilla E; Département d'Anatomie et Cytologie Pathologiques, Grenoble, France., Asselin-Labat ML; Personalized Oncology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Parkville, Australia., Persigehl T; Institute for Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Minna JD; University of Texas Southwestern Medical Center, Dallas, Texas, USA., Walczak H; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.; CECAD Cluster of Excellence, University of Cologne, Cologne, Germany.; Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, United Kingdom., Ullrich RT; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany., Fischer M; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, University Hospital Cologne, Medical Faculty, Cologne, Germany.; Center for Molecular Medicine Cologne (CMMC), Cologne, Germany., Reinhardt HC; Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, Essen, Germany., Wolf J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany., Büttner R; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany., Peifer M; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany.; Center for Molecular Medicine Cologne (CMMC), Cologne, Germany., George J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany.; Department of Head and Neck Surgery, Medical Faculty, University Hospital Cologne, Cologne, Germany., Thomas RK; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany.; German Cancer Consortium (DKTK), partner site Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2023 Nov 01; Vol. 133 (21). Date of Electronic Publication: 2023 Nov 01.
DOI: 10.1172/JCI170217
Abstrakt: The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer (SQLC) 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 SQLCs 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 were tumorigenic in both in vitro and in vivo models of lung cancer. Mechanistically, breakage-fusion-bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. Generally, tail-to-tail rearrangements within or in close proximity upstream of FGFR1 were associated with FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven SQLC. Specifically, we believe that FGFR1 ectodomain-deficient and FGFR1-centered amplifications caused by tail-to-tail rearrangements are a novel somatic genomic event that might be predictive of therapeutically relevant FGFR1 dependency.
Databáze: MEDLINE