The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

中文翻译：

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对具有 FGFR1 改变的各种低级别神经上皮肿瘤的综合分析揭示了形成玫瑰花结的胶质神经元肿瘤的独特分子特征。

编码成纤维细胞生长因子受体 1 的 FGFR1 基因已成为多种低级别神经上皮肿瘤 (LGNET) 亚型的发病机制中经常改变的癌基因，包括毛细胞星形细胞瘤、胚胎发育不良神经上皮肿瘤 (DNT)、玫瑰花结形成胶质神经元肿瘤 (RGNT)、和室外神经细胞瘤（EVN）。这些在 LGNET 中激活 FGFR1 的改变可以包括编码细胞内酪氨酸激酶结构域的外显子的串联复制、最常以 TACC1 作为伙伴的框内基因融合，或酪氨酸激酶结构域内的热点错义突变（在 p.N546 或 p .K656）。然而，这些不同的 FGFR1 事件对于各种 LGNET 亚型和伴随的遗传改变的特异性还没有得到很好的定义。在这里，我们对具有 FGFR1 改变的 30 个 LGNET 的不同队列进行了全面的基因组和表观基因组表征。我们发现，与其他具有 FGFR1 改变的 LGNET 相比，RGNT 具有独特的表观遗传特征，并且具有独特的特征，即 FGFR1 激酶域热点错义突变与 PIK3CA 或 PIK3R1 突变相结合，通常伴有 NF1 或 PTPN11 突变。相比之下，EVN 具有自己独特的表观遗传特征，其特征是 FGFR1-TACC1 融合作为单独的致病改变。此外，DNT 和毛细胞星形细胞瘤的特征是激酶结构域串联重复或热点错义突变，偶尔伴有 NF1 或 PTPN11 突变，但缺乏表征 RGNT 的伴随 PIK3CA 或 PIK3R1 突变。具有 FGFR1 改变的 LGNET 的神经胶质成分通常主要具有少突胶质细胞形态，并且许多具有 FGFR1 改变的毛细胞星形细胞瘤缺乏双相模式、毛状突起和 Rosenthal 纤维，这些都是具有 BRAF 突变或融合的毛细胞星形细胞瘤的特征。总之，该分析改进了具有 FGFR1 改变的 LGNET 的分类和组织病理学分层。