Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer
- Author(s)
- Malchers, F; FISCHER, M; Nogova, L; van Attekum, MH; Maas, L; Brägelmann, J; Bartenhagen, C; Girard, L; Bosco, G; Dahmen, I; Michels, S; Weeden, CE; Scheel, AH; Meder, L; Golfmann, K; Schuldt, P; Siemanowski, J; Rehker, J; Merkelbach-Bruse, S; Menon, R; Gautschi, O; Heuckmann, JM; Brambilla, E; Asselin-Labat, ML; Persigehl, T; Minna, JD; Walczak, H; Ullrich, RT; Reinhardt, HC; Wolf, J; Büttner, R; Peifer, M; George, J; Thomas, RK;
- Journal Title
- Journal of Clinical Investigation
- Abstract
- The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer 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 squamous cell lung carcinomas 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 tumorigenic in in-vitro and in-vivo. Mechanistically, Breakage-Fusion-Bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. However, only tumors with tail-to-tail rearrangements within or in close proximity upstream of FGFR1 exhibited FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven squamous cell lung cancer. Specifically, FGFR1 ectodomain deficient and FGFR1-centered amplifications caused by tail-to-tail rearrangements are novel somatic genomic event, which might be predictive of therapeutically relevant FGFR1 dependency.
- Publisher
- ASCI
- Keywords
- Drug therapy; Genetics; Lung cancer; Oncology
- Research Division(s)
- Personalised Oncology
- PubMed ID
- 37606995
- Publisher's Version
- https://doi.org/10.1172/jci170217
- Open Access at Publisher's Site
https://doi.org/10.1172/JCI170217- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-08-28 09:37:17
Last Modified: 2023-11-20 03:24:08