Abstract

Background

Actionable fibroblast growth factor receptor 3 (FGFR3)–transforming acidic coiled-coil protein 3 fusions (F3T3) are found in approximately 3% of gliomas, but their characteristics and prognostic significance are still poorly defined. Our goal was to characterize the clinical, radiological, and molecular profile of F3T3 positive diffuse gliomas.

Methods

We screened F3T3 fusion by real-time (RT)-PCR and FGFR3 immunohistochemistry in a large series of gliomas, characterized for main genetic alterations, histology, and clinical evolution. We performed a radiological and radiomic case control study, using an exploratory and a validation cohort.

Results

We screened 1162 diffuse gliomas (951 unselected cases and 211 preselected for FGFR3 protein immunopositivity), identifying 80 F3T3 positive gliomas. F3T3 was mutually exclusive with IDH mutation (P < 0.001) and EGFR amplification (P = 0.01), defining a distinct molecular cluster associated with CDK4 (P = 0.04) and MDM2 amplification (P = 0.03). F3T3 fusion was associated with longer survival for the whole series and for glioblastomas (median overall survival was 31.1 vs 19.9 mo, P = 0.02) and was an independent predictor of better outcome on multivariate analysis.F3T3 positive gliomas had specific MRI features, affecting preferentially insula and temporal lobe, and with poorly defined tumor margins. F3T3 fusion was correctly predicted by radiomics analysis on both the exploratory (area under the curve [AUC] = 0.87) and the validation MRI (AUC = 0.75) cohort. Using Cox proportional hazards models, radiomics predicted survival with a high C-index (0.75, SD 0.04), while the model combining clinical, genetic, and radiomic data showed the highest C-index (0.81, SD 0.04).

Conclusion

F3T3 positive gliomas have distinct molecular and radiological features, and better outcome.

中文翻译：

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FGFR3-TACC3融合胶质瘤的临床，分子和放射学特征。

摘要

背景

可操作的成纤维细胞生长因子受体3（FGFR3） -吨ransforming酸性卷曲螺旋蛋白3个融合物（F3T3）在神经胶质瘤的大约3％的被发现，但仍定义不清它们的特性和预后意义。我们的目标是表征F3T3阳性弥漫性神经胶质瘤的临床，放射学和分子特征。

方法

我们通过实时（RT）-PCR和FGFR3免疫组织化学在一系列神经胶质瘤中筛选了F3T3融合蛋白，其特征在于主要的遗传改变，组织学和临床进化。我们使用探索性和验证性队列进行了放射学和放射学病例对照研究。

结果

我们筛选了1162例弥漫性神经胶质瘤（951例未选病例和211例预选的FGFR3蛋白免疫阳性），确定了80例F3T3阳性神经胶质瘤。F3T3与IDH突变（P <0.001）和EGFR扩增（P = 0.01）互斥，定义了与CDK4（P = 0.04）和MDM2扩增（P = 0.03）相关的独特分子簇。F3T3融合与整个系列和胶质母细胞瘤的更长生存期相关（中位总生存期为31.1 vs 19.9 mo，P= 0.02）是多变量分析结果更好的独立预测因素.F3T3阳性神经胶质瘤具有特定的MRI特征，优先影响岛状和颞叶，并且肿瘤边缘定义不明确。F3T3融合是通过探索性（曲线下面积[AUC] = 0.87）和验证MRI（AUC = 0.75）队列中的放射组学分析正确预测的。使用Cox比例风险模型，放射线学家以高C指数（0.75，SD 0.04）预测生存，而结合临床，遗传和放射学数据的模型显示最高C指数（0.81，SD 0.04）。

结论

F3T3阳性神经胶质瘤具有独特的分子和放射学特征，且预后较好。