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

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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