{"doi":"10.1172/jci170217","title":"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.","journal":"Journal of Clinical Investigation","year":2023,"id":346564,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1087389,"name":"Lucia Nogová","orcid":"0000-0002-4502-1812","position":1,"is_corresponding":false},{"id":1087968,"name":"Martijn H.A. van Attekum","orcid":null,"position":2,"is_corresponding":false},{"id":1087390,"name":"Lukas Maas","orcid":"0000-0002-5830-6710","position":3,"is_corresponding":false},{"id":1087391,"name":"Johannes Brägelmann","orcid":"0000-0002-1306-2169","position":4,"is_corresponding":false},{"id":32735,"name":"Christoph Bartenhagen","orcid":"0000-0002-2522-1454","position":5,"is_corresponding":false},{"id":253870,"name":"Luc Girard","orcid":"0000-0002-6688-5281","position":6,"is_corresponding":false},{"id":606695,"name":"Graziella Bosco","orcid":"0000-0001-6601-4518","position":7,"is_corresponding":false},{"id":607111,"name":"Ilona Dahmen","orcid":null,"position":8,"is_corresponding":false},{"id":606687,"name":"Sebastian Michels","orcid":"0000-0003-3164-870X","position":9,"is_corresponding":false},{"id":1013759,"name":"Clare E. 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