Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.
Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.
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室管膜瘤是常见的儿童脑肿瘤，发生在整个神经系统，但最常见于儿科后脑。目前的标准治疗包括手术和放疗，但不包括细胞毒性化疗，因为它不能进一步提高生存率。47例后脑室管膜瘤的全基因组和全外显子组测序显示突变率极低，并且零显著的复发性体细胞单核苷酸变异。虽然没有复发性单核苷酸变异和局灶性拷贝数畸变，预后不良的后脑室管膜瘤表现出CpG岛甲基化表型。由CpG甲基化驱动的转录沉默仅集中在Polycomb抑制复合物2的靶标上，该复合物通过H3K27的三甲基化抑制分化基因的表达。CpG岛甲基化表型阳性的后脑室管膜瘤在体外和体内对靶向DNA或H3K27甲基化的临床药物有反应。我们的结论是，表观遗传修饰剂是这种致命的恶性肿瘤，这是表观遗传失调，但遗传平淡的第一个合理的治疗候选人。
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.
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影响因子：
15.9
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影响因子：
51.1
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Merchant, Thomas E.;Li, Chenghong;Xiong, Xiaoping;Kun, Larry E.;Boop, Frederic A.;Sanford, Robert A.
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Sanford, Robert A.