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Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer
Florian Malchers1, Lucia Nogova2, Martijn Ha van Attekum1
1University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany.
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.
Insights
Frequent 8p11-p12 amplifications in squamous cell lung cancer (SQLC) were linked to FGFR1 dependency. Novel ectodomain-deficient FGFR1 variants, driven by specific genomic rearrangements, explain treatment resistance and may predict therapeutic response.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Squamous cell lung cancer (SQLC) frequently exhibits 8p11-p12 amplifications, implicating FGFR1 as a potential therapeutic target.
- Clinical trials showed limited response to FGFR kinase inhibitors in patients with 8p11 amplification, necessitating a deeper understanding of FGFR1 dependency.
Purpose of the Study:
- To investigate the genomic mechanisms underlying FGFR1 dependency in SQLC with 8p11-p12 amplifications.
- To identify novel FGFR1 alterations and their association with therapeutic response in SQLC.
Main Methods:
- Deep genomic characterization of 52 SQLCs with 8p11-p12 amplification.
- Analysis of tumors from patients treated with FGFR inhibitors.
- In vitro and in vivo tumorigenicity assays for identified FGFR1 variants.
Main Results:
- Discovery of somatically altered FGFR1 variants with deleted exons 1-8 (ΔEC-FGFR1) due to intragenic tail-to-tail rearrangements.
- Expression of ΔEC-FGFR1 in tumors and demonstration of its tumorigenic potential.
- Association of tail-to-tail rearrangements near FGFR1 with FGFR1 dependency and limited inhibitor response.
Conclusions:
- Breakage-fusion-bridge cycles drive 8p11-p12 amplifications and associated rearrangements in SQLC.
- FGFR1 ectodomain-deficient variants and FGFR1-centered amplifications resulting from tail-to-tail rearrangements represent a novel mechanism of FGFR1-driven SQLC.
- These specific genomic events may serve as predictive biomarkers for FGFR1 dependency and therapeutic efficacy in SQLC.
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