TY - JOUR
T1 - Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer
AU - Malchers, Florian
AU - Nogova, Lucia
AU - van Attekum, Martijn H.A.
AU - Maas, Lukas
AU - Brägelmann, Johannes
AU - Bartenhagen, Christoph
AU - Girard, Luc
AU - Bosco, Graziella
AU - Dahmen, Ilona
AU - Michels, Sebastian
AU - Weeden, Clare E.
AU - Scheel, Andreas H.
AU - Meder, Lydia
AU - Golfmann, Kristina
AU - Schuldt, Philipp
AU - Siemanowski, Janna
AU - Rehker, Jan
AU - Merkelbach-Bruse, Sabine
AU - Menon, Roopika
AU - Gautschi, Oliver
AU - Heuckmann, Johannes M.
AU - Brambilla, Elisabeth
AU - Asselin-Labat, Marie Liesse
AU - Persigehl, Thorsten
AU - Minna, John D.
AU - Walczak, Henning
AU - Ullrich, Roland T.
AU - Fischer, Matthias
AU - Reinhardt, Hans Christian
AU - Wolf, Jürgen
AU - Büttner, Reinhard
AU - Peifer, Martin
AU - George, Julie
AU - Thomas, Roman K.
N1 - Publisher Copyright:
Copyright: © 2023, Malchers et al.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - 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 (ΔECFGFR1) 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.
AB - 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 (ΔECFGFR1) 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.
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U2 - 10.1172/JCI170217
DO - 10.1172/JCI170217
M3 - Article
C2 - 37606995
AN - SCOPUS:85175741300
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 21
M1 - e174171
ER -