Introduction: Activation of the fibroblast growth factor receptor (FGFR) family through fusion with various partners has been described in multiple cancer types, including NSCLC. FGFR inhibitors are currently being evaluated clinically for patients whose tumors harbor these fusions. Methods: Hybrid capture–based comprehensive genomic profiling was performed on 26,054 consecutive formalin‐fixed, paraffin‐embedded specimens of NSCLC. Results: FGFR fusions retaining the kinase domain were identified in 0.2% of NSCLC cases; they included 37 fibroblast growth factor receptor gene 3 (FGFR3)–transforming acidic coiled‐coil containing protein 3 gene (TACC3) fusion–positive cases, two fibroblast growth factor receptor 2 (FGFR2)–shootin 1 gene (KIAA1598 [also known as SHTN1]) fusion–positive cases, one BCL2 associated athanogene 4 gene (BAG4)–fibroblast growth factor receptor 1 gene (FGFR1) fusion–positive case, and 12 novel FGFR1, FGFR2, FGFR3, and fibroblast growth factor receptor 4 gene (FGFR4) fusion–positive cases. Co‐occurring EGFR or MNNG HOS Transforming gene (MET) alterations were observed in 8% of cases (four of 52), KRAS mutation was observed in three additional cases, and FGFR1 or FGFR3 amplification was observed in 10% of cases. The two patients with co‐occurring EGFR mutations were previously treated with EGFR inhibitors. One patient with a novel FGFR2–leucine zipper transcription factor like 1 gene (LZTFL1) fusion had a partial response to the pan‐FGFR inhibitor JNJ‐42756493 and remained progression‐free for 11 months. Conclusion: FGFR fusions were detected by using comprehensive genomic profiling in 0.2% of NSCLCs; they occurred primarily in the absence of other known driver alterations, or in a subset of cases, as likely mechanisms of acquired resistance. One patient with a novel FGFR2 fusion had clinical benefit from an investigational FGFR inhibitor, suggesting that these alterations may predict response to targeted therapies.

中文翻译：

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通过综合基因组分析检测非小细胞肺癌中已知和新的 FGFR 融合

简介：已在多种癌症类型（包括 NSCLC）中描述了通过与各种伙伴融合激活成纤维细胞生长因子受体 (FGFR) 家族。FGFR 抑制剂目前正在临床评估其肿瘤具有这些融合的患者。方法：对 26,054 个连续福尔马林固定、石蜡包埋的 NSCLC 标本进行了基于杂交捕获的综合基因组分析。结果：在 0.2% 的 NSCLC 病例中鉴定出保留激酶结构域的 FGFR 融合；它们包括 37 个成纤维细胞生长因子受体基因 3（FGFR3）-转化酸性卷曲螺旋蛋白 3 基因（TACC3）融合阳性病例，两个成纤维细胞生长因子受体 2（FGFR2）-shootin 1 基因（KIAA1598 [也称为 SHTN1 ]) 融合阳性病例，1 个 BCL2 相关的 athanogene 4 基因 (BAG4)-成纤维细胞生长因子受体 1 基因 (FGFR1) 融合阳性病例，以及 12 个新的 FGFR1、FGFR2、FGFR3 和成纤维细胞生长因子受体 4 基因 (FGFR4) 融合阳性病例。在 8% 的病例（52 例中的 4 例）中观察到同时发生的 EGFR 或 MNNG HOS 转化基因 (MET) 改变，在另外三个病例中观察到 KRAS 突变，在 10% 的病例中观察到 FGFR1 或 FGFR3 扩增。这两名同时发生 EGFR 突变的患者之前接受过 EGFR 抑制剂治疗。一名具有新型 FGFR2-亮氨酸拉链转录因子如 1 基因 (LZTFL1) 融合的患者对泛 FGFR 抑制剂 JNJ-42756493 有部分反应，并在 11 个月内保持无进展。结论：综合基因组分析在0.2%的NSCLC中检测到FGFR融合；它们主要发生在没有其他已知驱动程序改变的情况下，或在少数情况下，作为获得性抵抗的可能机制。一名患有新型 FGFR2 融合的患者从研究性 FGFR 抑制剂中获得了临床益处，这表明这些改变可能预测对靶向治疗的反应。