Bleeker Fonnet E, Lamba Simona, Zanon Carlo, Molenaar Remco J, Hulsebos Theo J M, Troost Dirk, van Tilborg Angela A, Vandertop W Peter, Leenstra Sieger, van Noorden Cornelis J F, Bardelli Alberto
Department of Oncology, University of Torino, SP 142, Km 3,95, Candiolo, Torino, 10060, Italy; Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
BMC Cancer. 2014 Sep 26;14:718. doi: 10.1186/1471-2407-14-718.
Glioblastoma is a highly malignant brain tumor for which no cure is available. To identify new therapeutic targets, we performed a mutation analysis of kinase genes in glioblastoma.
Database mining and a literature search identified 76 kinases that have been found to be mutated at least twice in multiple cancer types before. Among those we selected 34 kinase genes for mutation analysis. We also included IDH1, IDH2, PTEN, TP53 and NRAS, genes that are known to be mutated at considerable frequencies in glioblastoma. In total, 174 exons of 39 genes in 113 glioblastoma samples from 109 patients and 16 high-grade glioma (HGG) cell lines were sequenced.
Our mutation analysis led to the identification of 148 non-synonymous somatic mutations, of which 25 have not been reported before in glioblastoma. Somatic mutations were found in TP53, PTEN, IDH1, PIK3CA, EGFR, BRAF, EPHA3, NRAS, TGFBR2, FLT3 and RPS6KC1. Mapping the mutated genes into known signaling pathways revealed that the large majority of them plays a central role in the PI3K-AKT pathway.
The knowledge that at least 50% of glioblastoma tumors display mutational activation of the PI3K-AKT pathway should offer new opportunities for the rational development of therapeutic approaches for glioblastomas. However, due to the development of resistance mechanisms, kinase inhibition studies targeting the PI3K-AKT pathway for relapsing glioblastoma have mostly failed thus far. Other therapies should be investigated, targeting early events in gliomagenesis that involve both kinases and non-kinases.
胶质母细胞瘤是一种高度恶性的脑肿瘤，目前尚无治愈方法。为了确定新的治疗靶点，我们对胶质母细胞瘤中的激酶基因进行了突变分析。
通过数据库挖掘和文献检索，确定了76种激酶，这些激酶在多种癌症类型中至少有两次被发现发生突变。在这些激酶中，我们选择了34个激酶基因进行突变分析。我们还纳入了异柠檬酸脱氢酶1（IDH1）、异柠檬酸脱氢酶2（IDH2）、磷酸酶和张力蛋白同源物（PTEN）、肿瘤蛋白p53（TP53）和神经母细胞瘤RAS病毒癌基因同源物（NRAS），这些基因在胶质母细胞瘤中已知有相当高的突变频率。对来自109例患者的113个胶质母细胞瘤样本和16个高级别胶质瘤（HGG）细胞系中的39个基因的174个外显子进行了测序。
我们的突变分析发现了148个非同义体细胞突变，其中25个在胶质母细胞瘤中以前未被报道过。在TP53、PTEN、IDH1、磷脂酰肌醇-3-激酶催化亚基α（PIK3CA）、表皮生长因子受体（EGFR）、B-Raf原癌基因（BRAF）、Ephrin A3受体（EPHA3）、NRAS、转化生长因子β受体Ⅱ（TGFBR2）、FMS样酪氨酸激酶3（FLT）和核糖体蛋白S6激酶β-1（RPS6KC1）中发现了体细胞突变。将突变基因映射到已知的信号通路中发现，其中绝大多数在磷脂酰肌醇-3-激酶-蛋白激酶B（PI3K-AKT）通路中起核心作用。
至少50%的胶质母细胞瘤肿瘤显示PI3K-AKT通路的突变激活这一认识，应为胶质母细胞瘤治疗方法的合理开发提供新机会。然而，由于耐药机制的发展，针对复发性胶质母细胞瘤的PI3K-AKT通路的激酶抑制研究迄今大多失败。应研究其他疗法，针对涉及激酶和非激酶的胶质瘤发生早期事件。
