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@ARTICLE{Malchers:285132,
      author       = {F. Malchers and L. Nogova and M. H. van Attekum and L. Maas
                      and J. Brägelmann and C. Bartenhagen and L. Girard and G.
                      Bosco and I. Dahmen and S. Michels and C. E. Weeden and A.
                      H. Scheel and L. Meder and K. Golfmann and P. Schuldt and J.
                      Siemanowski and J. Rehker and S. Merkelbach-Bruse and R.
                      Menon and O. Gautschi and J. M. Heuckmann and E. Brambilla
                      and M.-L. Asselin-Labat and T. Persigehl and J. D. Minna and
                      H. Walczak and R. T. Ullrich and M. Fischer and H. C.
                      Reinhardt and J. Wolf and R. Büttner and M. Peifer and J.
                      George and R. K. Thomas$^*$},
      title        = {{S}omatic rearrangements causing oncogenic ectodomain
                      deletions of {FGFR}1 in squamous cell lung cancer.},
      journal      = {The journal of clinical investigation},
      volume       = {133},
      number       = {21},
      issn         = {0021-9738},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DKFZ-2023-02256},
      pages        = {e170217},
      year         = {2023},
      abstract     = {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.},
      keywords     = {Humans / Lung Neoplasms: drug therapy / Lung Neoplasms:
                      genetics / Lung Neoplasms: pathology / Gene Amplification /
                      Carcinoma, Non-Small-Cell Lung: drug therapy / Carcinoma,
                      Non-Small-Cell Lung: genetics / Carcinoma, Squamous Cell:
                      genetics / Carcinoma, Squamous Cell: pathology / Receptor,
                      Fibroblast Growth Factor, Type 1: genetics / Receptor,
                      Fibroblast Growth Factor, Type 1: metabolism / Protein
                      Kinase Inhibitors: pharmacology / Epithelial Cells:
                      metabolism / Drug therapy (Other) / Genetics (Other) / Lung
                      cancer (Other) / Oncology (Other) / Receptor, Fibroblast
                      Growth Factor, Type 1 (NLM Chemicals) / Protein Kinase
                      Inhibitors (NLM Chemicals) / FGFR1 protein, human (NLM
                      Chemicals)},
      cin          = {HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)HD01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37606995},
      pmc          = {pmc:PMC10617767},
      doi          = {10.1172/JCI170217},
      url          = {https://inrepo02.dkfz.de/record/285132},
}