A subset of glioblastomas (GBMs) harbors potentially druggable oncogenic FGFR3-TACC3 (F3T3) fusions. However, their associated molecular and clinical features are poorly understood. Here we analyze the frequency of F3T3-fusion positivity, its associated genetic and methylation profiles, and its impact on survival in 906 IDH-wildtype GBM patients. We establish an F3T3 prevalence of 4.1% and delineate its associations with cancer signaling pathway alterations. F3T3-positive GBMs had lower tumor mutational and copy-number alteration burdens than F3T3-wildtype GBMs. Although F3T3 fusions were predominantly mutually exclusive with other oncogenic RTK pathway alterations, they did rarely co-occur with EGFR amplification. They were less likely to harbor TP53 alterations. By methylation profiling, they were more likely to be assigned the mesenchymal or RTK II subclass. Despite being older at diagnosis and having similar frequencies of MGMT promoter hypermethylation, patients with F3T3-positive GBMs lived about 8 months longer than those with F3T3-wildtype tumors. While consistent with IDH-wildtype GBM, F3T3-positive GBMs exhibit distinct biological features, underscoring the importance of pursuing molecular studies prior to clinical trial enrollment and targeted treatment.

中文翻译：

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具有 FGFR3-TACC3 融合的 IDH 野生型胶质母细胞瘤的遗传和表观遗传景观

胶质母细胞瘤 (GBM) 的一个子集具有潜在的可药物致癌 FGFR3-TACC3 (F3T3) 融合。然而，对它们相关的分子和临床特征知之甚少。在这里，我们分析了 F3T3 融合阳性的频率、其相关的遗传和甲基化谱，以及它对 906 名 IDH 野生型 GBM 患者的生存率的影响。我们建立了 4.1% 的 F3T3 流行率，并描绘了它与癌症信号通路改变的关联。F3T3 阳性 GBM 的肿瘤突变和拷贝数改变负担低于 F3T3 野生型 GBM。尽管 F3T3 融合主要与其他致癌 RTK 通路改变互斥，但它们很少与 EGFR 扩增同时发生。他们不太可能携带 TP53 改变。通过甲基化分析，他们更有可能被分配到间充质或 RTK II 亚类。尽管诊断时年龄较大且 MGMT 启动子高甲基化的频率相似，但 F3T3 阳性 GBM 患者的寿命比 F3T3 野生型肿瘤患者长约 8 个月。虽然与 IDH 野生型 GBM 一致，但 F3T3 阳性 GBM 表现出不同的生物学特征，强调了在临床试验注册和靶向治疗之前进行分子研究的重要性。