Nature2014-06-25 5:04 PM

儿童室管膜瘤的基因组分析2 C11orf95–RELA fusions drive oncogenic NF-κB signalling in ependymoma

论文摘要 


在本期Nature上,两个小组发表了对室管膜瘤所做的独立基因组分析。室管膜瘤是在整个神经系统中出现的一种肿瘤,但在儿童后脑中最常见。Mack等人在47个后脑室管膜瘤中发现总体突变率较低,且没有显著的频发突变。但“后窝Group A肿瘤”(主要在婴儿中出现的一个子类,预后较差) 因一个CpG孤岛甲基剂表现型而显得与众不同。这个子类被发现对以表观遗传修饰为目标的各种不同化合物较敏感,其中包括在小鼠异种移植模型中有效果的一种EZH2抑制药物。Parker等人在大约70%的“幕上瘤”中发现了C11orf95–RELA融合基因,但没有在其他室管膜瘤子类中发现。基因融合是通过“染色体碎裂”(chromothripsis)发生的,导致可结构性激发NF-B信号作用的一种融合蛋白的表达。在一个小鼠模型中,C11orf95–RELA在神经干细胞中的表达导致脑瘤的形成。这些发现说明NF-B信号作用对这种类型的室管膜瘤患者是一个可能的治疗目标。


Abstract 


Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95–RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95–RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95–RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.

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