Oncogenic BRAF fusions have emerged as an alternate mechanism for BRAF activation in melanomas and other cancers. A number of BRAF fusions with different 5' gene partners and BRAF exon breakpoints have been described, but the effects of different partners and breakpoints on cancer phenotypes and treatment responses has not been well characterized. Targeted RNA sequencing was used to screen 60 melanoma patient-derived xenograft (PDX) models for BRAF fusions. We identified three unique BRAF fusions, including a novel SEPT3-BRAF fusion, occurring in four tumors (4/60, 6.7%), all of which were "pan-negative" (lacking other common mutations) (4/18, 22.2%). The BRAF fusion PDX models showed variable growth rates and responses to MAPK inhibitors in vivo. Overexpression of BRAF fusions identified in our study, as well as other BRAF fusions previously identified in melanomas, resulted in a high degree of variability in 2D proliferation and 3D invasion between the different fusions. While exogenously expressed BRAF fusions all responded to MAPK inhibition in vitro, we observed potential differences in signaling and feedback mechanisms. In summary, BRAF fusions are actionable therapeutic targets, however there are significant differences in phenotypes, treatment responses, and signaling which may be clinically relevant.

中文翻译：

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在黑色素瘤中发现的 BRAF 融合具有不同的治疗反应和表型。

致癌 BRAF 融合已成为黑色素瘤和其他癌症中 BRAF 激活的替代机制。已经描述了许多具有不同 5' 基因伴侣和 BRAF 外显子断点的 BRAF 融合，但不同伴侣和断点对癌症表型和治疗反应的影响尚未得到很好的表征。靶向 RNA 测序用于筛选 60 个黑色素瘤患者来源的异种移植 (PDX) 模型以进行 BRAF 融合。我们鉴定了三种独特的 BRAF 融合，包括一种新型 SEPT3-BRAF 融合，发生在四种肿瘤中（4/60, 6.7%），所有这些都是“泛阴性”（缺乏其他常见突变）（4/18, 22.2% ）。BRAF 融合 PDX 模型在体内显示出可变的生长速率和对 MAPK 抑制剂的反应。在我们的研究中发现 BRAF 融合的过度表达，以及先前在黑色素瘤中发现的其他 BRAF 融合，导致不同融合之间 2D 增殖和 3D 侵袭的高度可变性。虽然外源表达的 BRAF 融合在体外都对 MAPK 抑制有反应，但我们观察到信号传导和反馈机制的潜在差异。总之，BRAF 融合是可行的治疗靶点，但在表型、治疗反应和可能与临床相关的信号传导方面存在显着差异。