Zheng Tuyu, Ghasemi David R, Okonechnikov Konstantin, Korshunov Andrey, Sill Martin, Maass Kendra K, Benites Goncalves da Silva Patricia, Ryzhova Marina, Gojo Johannes, Stichel Damian, Arabzade Amir, Kupp Robert, Benzel Julia, Taya Shinichiro, Adachi Toma, Shiraishi Ryo, Gerber Nicolas U, Sturm Dominik, Ecker Jonas, Sievers Philipp, Selt Florian, Chapman Rebecca, Haberler Christine, Figarella-Branger Dominique, Reifenberger Guido, Fleischhack Gudrun, Rutkowski Stefan, Donson Andrew M, Ramaswamy Vijay, Capper David, Ellison David W, Herold-Mende Christel C, Schüller Ulrich, Brandner Sebastian, Driever Pablo Hernáiz, Kros Johan M, Snuderl Matija, Milde Till, Grundy Richard G, Hoshino Mikio, Mack Stephen C, Gilbertson Richard J, Jones David T W, Kool Marcel, von Deimling Andreas, Pfister Stefan M, Sahm Felix, Kawauchi Daisuke, Pajtler Kristian W
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
Cancer Discov. 2021 Sep;11(9):2230-2247. doi: 10.1158/2159-8290.CD-20-0963. Epub 2021 Apr 20.
Molecular groups of supratentorial ependymomas comprise tumors with or -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 as a partner gene. Somatic overexpression of -associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation , and cross-species comparative analyses identified 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: 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 fusion-positive tumors, such as GLI2..
幕上室管膜瘤的分子亚群包括具有或涉及融合的肿瘤以及融合阴性的室管膜下瘤。然而，由于未检测到典型融合和/或基于DNA甲基化的分类不明确，幕上室管膜瘤偶尔无法轻易归入这些亚群中的任何一个。一项针对规模前所未有的队列的无偏倚方法揭示了不同的甲基化簇，这些簇由具有室管膜特征但也有各种其他组织学特征的肿瘤组成，这些肿瘤含有作为伙伴基因共享的替代易位。在发育中的大脑皮层中，与相关融合基因的体细胞过表达能够诱导肿瘤形成，跨物种比较分析确定在所有肿瘤中是肿瘤发生的关键下游调节因子。用三氧化二砷靶向GLI2可延长荷瘤动物的生存期，表明在ZFTA融合阳性肿瘤中存在潜在的治疗弱点。意义：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发挥作用。通过建立代表性的小鼠模型，我们确定了融合阳性肿瘤共有的潜在治疗靶点，如GLI2。
