Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas
Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas
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DOI：
10.1158/2159-8290.cd-20-0963
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发表时间：
2021-09-01
期刊：
影响因子：
28.2
通讯作者：
Pajtler, Kristian W.
中科院分区：
文献类型：
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作者：
Zheng, Tuyu;Ghasemi, David R.;Pajtler, Kristian W.
幕上室管膜瘤的分子组包括涉及ZFTA-RELA或YAP 1融合的肿瘤和融合阴性的室管膜下瘤。然而，偶尔幕上室管膜瘤不能很容易地分配到任何这些组由于缺乏检测的一个典型的融合和/或模糊的DNA甲基化为基础的分类。一个无偏见的方法与前所未有的规模的队列显示不同的甲基化集群组成的肿瘤室管膜，但也有各种其他组织学特征包含替代易位，共享ZFTA作为一个合作伙伴基因。在发育中的大脑皮层中ZFTA相关融合基因的体细胞过表达能够在体内诱导肿瘤形成，并且跨物种比较分析将GLI 2鉴定为所有肿瘤中肿瘤发生的关键下游调节因子。靶向GLI 2与三氧化二砷导致荷瘤动物的生存期延长，表明ZFTA融合阳性tumors.SIGNIFICANCE的潜在治疗脆弱性：ZFTA-RELA融合是幕上室管膜瘤的标志性特征。我们发现ZFTA在具有各种组织学特征的幕上肿瘤的致癌融合中作为替代转录激活因子的伙伴。通过建立代表性的小鼠模型，我们确定了ZFTA融合阳性肿瘤（如GLI 2）共有的潜在治疗靶点。
Molecular groups of supratentorial ependymomas comprise tumors with ZFTA-RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histologic features containing alternative translocations that shared ZFTA as a partner gene. Somatic overexpression of ZFTA-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation in vivo, and cross-species comparative analyses identified GLI2 as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors.SIGNIFICANCE: ZFTA-RELA fusions are a hallmark feature of supratentorial ependymoma. We find that ZFTA acts as a partner for alternative transcriptional activators in oncogenic fusions of supratentorial tumors with various histologic characteristics. Establishing representative mouse models, we identify potential therapeutic targets shared by ZFTA fusion-positive tumors, such as GLI2.