Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer
Florian Malchers, … , Julie George, Roman K. Thomas
Florian Malchers, … , Julie George, Roman K. Thomas
Published August 22, 2023
Citation Information: J Clin Invest. 2023;133(21):e170217. https://doi.org/10.1172/JCI170217.
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Research Article Genetics Oncology

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

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.

Authors

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

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Figure 1

Tail-to-tail rearrangements in patients responding to FGFR inhibition.

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Tail-to-tail rearrangements in patients responding to FGFR inhibition. (...
(A) Overview of the study cohorts. (B) Kaplan-Meier curve showing progression-free survival of patients with 8p11-amplified SQLC treated with the FGFR inhibitors BGJ398 or GW786034 (TUM006). FGFR1 amplification was determined by FISH. Asterisk indicates that treatment was stopped because of toxicity. (C) Tumor volume change for patients with FGFR1-amplified SQLC treated with BGJ398 (Response Evaluation Criteria in Solid Tumors [RECIST] criteria). Tumor progression (red) and durable response (blue) following FGFR inhibition. TUM003 and TUM007 died during treatment with no sign of response. One patient (TUM006) was treated off-label (asterisk indicates that no RECIST data are available). Tumor shrinkage was estimated on CT scans (Supplemental Figure 1). (D and E) CT scans of patient TUM005 without a response and patient TUM004 with a durable response. (F) Copy number (CN) for 6 patients with progressive disease and 4 patients with a durable response to FGFR inhibition (5, 6). Red arrows indicate samples with tail-to-tail rearrangements within FGFR1 (highlighted by a green frame). (G) Copy number plot magnified at the FGFR1 locus (615x sequencing coverage). Patient TUM004 had a response to FGFR inhibition with BGJ398. Normal exon structure of FGFR1 (middle), resulting in genomic rearrangement (bottom), and the location of the detected breaks are indicated by arrows, as are the resulting rearrangements. (H) Copy number plot magnified at the FGFR1 locus (558x sequencing coverage). Tumor sample TUM006 was obtained from a patient responding to off-label treatment with GW786034. Normal exon structure (middle), the resulting genomic rearrangement (bottom), and the location of the detected breaks and resulting rearrangements are indicated by arrows. Image shows p-FGFR1 by IHC image (scale bar: 100 μm). (I) Transcript of FGFR1 WT (ENST00000397091.9, top) and transcripts of FGFR1 found in treatment-naive patient samples (middle and bottom) with possible ATG start codons (TAC motive from right to left; FGFR1 is located on the negative strand). Light blue indicates UTRs.