Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma.
Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma.
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DOI：
10.1038/onc.2009.73
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发表时间：
2009-05-21
期刊：
影响因子：
8
通讯作者：
Collins VP
中科院分区：
文献类型：
--
作者：
Jones DT;Kocialkowski S;Liu L;Pearson DM;Ichimura K;Collins VP
毛细胞星形细胞瘤（PAs）是世卫组织一级恶性肿瘤，是5-19岁儿童中最常见的中枢神经系统肿瘤。最近的报道强调了PAs中MAPK通路激活的重要性，特别是通过串联复制导致致癌BRAF融合基因。在这里，我们报告了导致PAs中MAPK激活的两种可选机制。首先，与常见的BRAF融合惊人的相似，在3p25处观察到串联重复，这在SRGAP3和RAF1之间产生了框架内的致癌融合。这种融合包括Raf1激酶结构域，与野生型Raf1相比，显示出更高的激酶活性。其次，BRAF密码子598处一个新的3bp插入模仿热点V600E突变，产生一个转化的、组成活性的BRAF激酶。虽然这两种改变并不常见，但它们使Ras/Raf信号通路被“击中”的病例数量从我们的44例（82%）增加到36例，证实了其对毛细胞星形细胞瘤发展的核心重要性。
Pilocytic astrocytomas (PAs), WHO malignancy grade I, are the most frequently occurring central nervous system tumour in 5-19 year-olds. Recent reports have highlighted the importance of MAPK pathway activation in PAs, particularly through a tandem duplication leading to an oncogenic BRAF fusion gene. Here we report two alternative mechanisms resulting in MAPK activation in PAs. Firstly, in striking similarity to the common BRAF fusion, a tandem duplication at 3p25 was observed, which produces an in-frame oncogenic fusion between SRGAP3 and RAF1. This fusion includes the Raf1 kinase domain, and shows elevated kinase activity when compared with wild-type Raf1. Secondly, a novel 3bp insertion at codon 598 in BRAF mimics the hotspot V600E mutation to produce a transforming, constitutively active BRaf kinase. Whilst these two alterations are not common, they bring the number of cases with an identified ‘hit’ on the Ras/Raf signalling pathway to 36 from our series of 44 (82%), confirming its central importance to the development of pilocytic astrocytomas.
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