Departments of Neuropathology and Biometry and Medical Informatics, Otto-von-Guericke University, Magdeburg,Germany; Departments of Neuropathology and Neurosurgery, Hannover Medical School, Hannover, Germany; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Department of Neurosurgery, Krankenhaus Köln MerheimKliniken der Stadt Köln gGmbH, University of Witten/Herdecke, Köln, Germany; Center for Behavioural Brain Sciences, Magdeburg,Germany.
Neuro Oncol. 2017 Aug 1;19(8):1088-1096. doi: 10.1093/neuonc/nox018.
Skull base meningiomas are considered to be difficult for surgical treatment. We wondered whether genetic alterations recently identified in benign non-NF2-mutated World Health Organization (WHO) grade I meningiomas are related to clinical features of skull base meningiomas and whether druggable signaling pathways are activated.
We analyzed 93 skull base meningiomas (82 WHO grade I, 11 WHO grade II) for mutations of hot spots or the most relevant exons of AKT1, KLF4/TRAF7, SMO, PI3K, and the TERT promoter.
The AKT1E17K mutation was present in 31% of patients and was related to meningothelial histology. AKT1E17K had a negative effect on the time to tumor recurrence. Analyses of activated signaling proteins revealed among AKT1E17K tumors a significantly higher rate of phospho-mammalian target of rapamycin (mTOR) and phospho-p70S6K+ tumors. AKT1E17K tumors with immunoexpression of phospho-extracellular signal-regulated kinase 1 or 2 (ERK1/2) were characterized by significantly shorter time to tumor recurrence compared with AKT1wt tumors expressing phospho-ERK1/2 (P = .046). KLF4 mutations (K409Q) were present in 11.8% of cases, with significant association to the secretory/transitional subtype (P < .001). The presence of the KLF4 K409Q mutation was associated with favorable outcome. One phosphatidylinositol-3 kinase (PI3K) mutation but no SMO or TERT promoter mutation was found.
AKT1E17K mutation is frequent in skull base meningiomas, results in activation of the mTOR and ERK1/2 signaling pathways, and has negative impact on tumor recurrence. Patients with skull base meningiomas with AKT1E17K mutation might benefit from additional treatment targeting the mTOR pathway. Generally, the PI3K-Akt-mTOR axis might be a potential target for kinase inhibitors in these tumors.
颅底脑膜瘤被认为是手术治疗的难点。我们想知道，最近在良性非 NF2 突变的世界卫生组织（WHO）I 级脑膜瘤中发现的遗传改变是否与颅底脑膜瘤的临床特征有关，以及是否激活了可用药的信号通路。
我们分析了 93 例颅底脑膜瘤（82 例 WHO I 级，11 例 WHO II 级）的 AKT1、KLF4/TRAF7、SMO、PI3K 和 TERT 启动子热点或最相关外显子的突变。
AKT1E17K 突变存在于 31%的患者中，与脑膜上皮组织学有关。AKT1E17K 对肿瘤复发时间有负面影响。分析激活的信号蛋白发现，在 AKT1E17K 肿瘤中，磷酸化哺乳动物靶标雷帕霉素（mTOR）和磷酸化 p70S6K+肿瘤的比例明显更高。与表达磷酸化 ERK1/2 的 AKT1wt 肿瘤相比，免疫组化显示磷酸化细胞外信号调节激酶 1 或 2（ERK1/2）的 AKT1E17K 肿瘤的肿瘤复发时间明显更短（P=0.046）。KLF4 突变（K409Q）存在于 11.8%的病例中，与分泌/过渡亚型显著相关（P<0.001）。KLF4 K409Q 突变的存在与良好的预后相关。发现一个磷脂酰肌醇-3 激酶（PI3K）突变，但没有 SMO 或 TERT 启动子突变。
AKT1E17K 突变在颅底脑膜瘤中很常见，导致 mTOR 和 ERK1/2 信号通路的激活，并对肿瘤复发有负面影响。有 AKT1E17K 突变的颅底脑膜瘤患者可能受益于针对 mTOR 通路的额外治疗。一般来说，PI3K-Akt-mTOR 轴可能是这些肿瘤中激酶抑制剂的潜在靶点。
