在鳞状细胞肺癌中频繁发现了8p11-p12放大，从而引发了FGFR1作为治疗靶点的希望。在一项临床试验中，只有11%的8p11放大患者（通过FISH检测）对FGFR激酶抑制剂治疗有反应。为了解FGFR1依赖机制，我们对52例8p11-p12放大的鳞状细胞肺癌进行了深度基因组表征，其中包括10例接受FGFR抑制剂治疗的患者的肿瘤。我们发现FGFR1的部分改变型别包括exo1-8的缺失，其结果是由内源内外领区重排引起的。这些缺乏外领域能力的FGFR1变异体（ΔEC-FGFR1）在受影响的肿瘤中表达并在体外和体内具有致瘤性。机理上，断裂融合桥是8p11-p12放大的来源，常见的头对头和尾对尾重排引起。然而，只有在FGFR1之内或紧邻上游发生的尾对尾重排的肿瘤表现出对FGFR1的依赖性。因此，塑造8p11-p12放大区域结构的基因组事件为FGFR1驱动的鳞状细胞肺癌的出现提供了机械解释。具体而言，FGFR1缺乏外领域和以FGFR1为中心的放大是由尾对尾重排引起的新的体细胞基因组事件，可能对预测与治疗相关的FGFR1依赖性有预测作用。

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.