Institute of Neuropathology, University Hospital Münster, Münster, Germany.
Clin Cancer Res. 2011 Jun 1;17(11):3631-7. doi: 10.1158/1078-0432.CCR-11-0175. Epub 2011 Apr 14.
Ependymomas are glial tumors of presumably radial glial origin that share morphologic similarities with ependymal cells. The molecular genetics of ependymomas of supratentorial, infratentorial, and spinal location is heterogeneous. We aimed at identifying pathways operative in the development of infratentorial ependymomas.
To do so, gene expression profiles of tumor cells laser microdissected from infratentorial ependymomas (n = 15) were compared with that of nonneoplastic ependymal cells laser microdissected from autopsy tissue (n = 7).
Among 31 genes significantly overexpressed (>5-fold) in ependymomas, transcription factor EVI1 (ecotropic viral integration site 1) showed the highest overexpression (35-fold). Evi-1 protein expression could be confirmed in formalin-fixed, paraffin-embedded samples of 26 of 28 infratentorial ependymomas but only in 7 of 47 nonependymal glial tumors (P < 0.001). Furthermore, MDS1/EVI1 fusion transcripts were detectable in 17 of 28 infratentorial ependymomas and significantly correlated with MGMT (O6-methylguanine-DNA-methyltransferase) promoter hypermethylation (P < 0.05). In primary infratentorial ependymoma cells, transfection with EVI1-specific siRNAs resulted in significant growth inhibition [48 hours: 87% ± 2% and 74% ± 10% as compared with control (mean ± SD; P < 0.001)]. The prognostic role of EVI1 could further be validated in an independent cohort of 39 infratentorial and 26 supratentorial ependymomas on the basis of mRNA expression profiling. Although in supratentorial ependymomas EVI1 expression status had no prognostic impact, in infratentorial ependymomas, high EVI1 expression was associated with shorter overall survival and progression-free survival.
To conclude, the transcription factor Evi-1 is overexpressed in infratentorial ependymomas, promotes proliferation of ependymal tumor cells, and is prognostically unfavorable.
室管膜瘤是一种源自放射状胶质细胞的神经胶质肿瘤，与室管膜细胞具有相似的形态学特征。发生于幕上、幕下和脊髓的室管膜瘤的分子遗传学具有异质性。本研究旨在确定幕下室管膜瘤发生的相关途径。
为了实现这一目标，对激光微切割自幕下室管膜瘤（n = 15）的肿瘤细胞和从尸检组织中激光微切割的非肿瘤性室管膜细胞（n = 7）的基因表达谱进行了比较。
在 31 个显著过表达（> 5 倍）的基因中，转录因子 EVI1（ectropic viral integration site 1）的过表达水平最高（35 倍）。Evi-1 蛋白表达可在 28 例幕下室管膜瘤中 26 例福尔马林固定、石蜡包埋样本中得到确认，但在 47 例非室管膜神经胶质肿瘤中仅 7 例得到确认（P < 0.001）。此外，在 17 例幕下室管膜瘤中可检测到 MDS1/EVI1 融合转录本，与 MGMT（O6-甲基鸟嘌呤-DNA-甲基转移酶）启动子甲基化高度相关（P < 0.05）。在原发性幕下室管膜瘤细胞中，用 EVI1 特异性 siRNA 转染可导致显著的生长抑制[48 小时：与对照组相比分别为 87% ± 2%和 74% ± 10%（平均值 ± 标准差；P < 0.001）]。在基于 mRNA 表达谱的 39 例幕下和 26 例幕上室管膜瘤的独立队列中，进一步验证了 EVI1 的预后作用。尽管在幕上室管膜瘤中，EVI1 表达状态无预后影响，但在幕下室管膜瘤中，EVI1 高表达与总生存期和无进展生存期缩短相关。
综上所述，转录因子 Evi-1 在幕下室管膜瘤中过表达，促进室管膜瘤细胞增殖，且具有不良预后。
