Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

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GroupB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-REM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-κB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-κB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。%Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.