Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer.
Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer.
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DOI：
10.1172/jci170217
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发表时间：
2023-11-01
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影响因子：
--
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中科院分区：
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在鳞状细胞肺癌(SQLC)中发现了频繁的8p11-p12扩增，这让人们燃起了希望，即位于该扩增子内部的FGFR1可能是一个治疗靶点。在一项临床试验中，只有11%的8p11扩增患者(FISH检测到)对FGFR激酶抑制剂治疗有反应。为了了解FGFR1依赖的机制，我们对52个8p11-p12扩增的SQLCs进行了深入的基因组分析，其中包括10个来自接受FGFR抑制剂治疗的患者的肿瘤。我们发现了由于基因内尾对尾重排导致的FGFR1外显子1-8缺失的体细胞变化变异体。这些胞外结构域缺陷的FGFR1变异体(Δ，EC-FGFR1a)在受影响的肿瘤中表达，并在体外和体内肺癌模型中均有致瘤作用。从机制上讲，断裂融合桥是8p11-p12扩增的来源，这是由于频繁的头到头和尾到尾的重排造成的。一般来说，FGFR1上游或上游的尾巴到尾巴的重排与FGFR1依赖有关。因此，塑造8p11-p12扩增子结构的基因组事件为FGFR1驱动的SQLC的出现提供了一种机械解释。具体地说，我们认为尾对尾重排引起的FGFR1胞外结构域缺陷和FGFR1中心扩增是一种新的体细胞基因组事件，可能预测治疗相关的FGFR1依赖。
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.
影响因子：
12.3
作者：
Fernandez-Cuesta L;Sun R;Menon R;George J;Lorenz S;Meza-Zepeda LA;Peifer M;Plenker D;Heuckmann JM;Leenders F;Zander T;Dahmen I;Koker M;Schöttle J;Ullrich RT;Altmüller J;Becker C;Nürnberg P;Seidel H;Böhm D;Göke F;Ansén S;Russell PA;Wright GM;Wainer Z;Solomon B;Petersen I;Clement JH;Sänger J;Brustugun OT;Helland Å;Solberg S;Lund-Iversen M;Buettner R;Wolf J;Brambilla E;Vingron M;Perner S;Haas SA;Thomas RK
通讯作者：
Thomas RK