From the Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.
Department of Pediatrics, University of Colorado School of Medicine, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA.
J Neuropathol Exp Neurol. 2021 Dec 29;80(12):1099-1107. doi: 10.1093/jnen/nlab110.
Brain tumors are the most common solid tumor in children, and low-grade gliomas (LGGs) are the most common childhood brain tumor. Here, we report on 3 patients with LGG harboring previously unreported or rarely reported RAF fusions: FYCO1-RAF1, CTTNBP2-BRAF, and SLC44A1-BRAF. We hypothesized that these tumors would show molecular similarity to the canonical KIAA1549-BRAF fusion that is the most widely seen alteration in pilocytic astrocytoma (PA), the most common pediatric LGG variant, and that this similarity would include mitogen-activated protein kinase (MAPK) pathway activation. To test our hypothesis, we utilized immunofluorescent imaging and RNA-sequencing in normal brain, KIAA1549-BRAF-harboring tumors, and our 3 tumors with novel fusions. We performed immunofluorescent staining of ERK and phosphorylated ERK (p-ERK), identifying increased p-ERK expression in KIAA1549-BRAF fused PA and the novel fusion samples, indicative of MAPK pathway activation. Geneset enrichment analysis further confirmed upregulated downstream MAPK activation. These results suggest that MAPK activation is the oncogenic mechanism in noncanonical RAF fusion-driven LGG. Similarity in the oncogenic mechanism suggests that LGGs with noncanonical RAF fusions are likely to respond to MEK inhibitors.
脑肿瘤是儿童中最常见的实体肿瘤,而低级别胶质瘤(LGG)是儿童中最常见的脑肿瘤。在这里,我们报告了 3 例携带先前未报道或很少报道的 RAF 融合的 LGG 患者:FYCO1-RAF1、CTTNBP2-BRAF 和 SLC44A1-BRAF。我们假设这些肿瘤与最常见于毛细胞星形细胞瘤(PA)的经典 KIAA1549-BRAF 融合具有分子相似性,PA 是最常见的儿童 LGG 变体,这种相似性将包括丝裂原活化蛋白激酶(MAPK)通路的激活。为了验证我们的假设,我们在正常大脑、携带 KIAA1549-BRAF 的肿瘤以及我们的 3 例具有新型融合的肿瘤中利用免疫荧光成像和 RNA 测序进行了研究。我们对 ERK 和磷酸化 ERK(p-ERK)进行了免疫荧光染色,发现在 KIAA1549-BRAF 融合的 PA 和新型融合样本中 p-ERK 的表达增加,表明 MAPK 通路的激活。基因集富集分析进一步证实了下游 MAPK 激活的上调。这些结果表明,MAPK 激活是驱动非典型 RAF 融合的 LGG 的致癌机制。致癌机制的相似性表明,具有非典型 RAF 融合的 LGG 可能对 MEK 抑制剂有反应。