Function and regulation of the glioma methylator phenotype (G-CIMP)

神经胶质瘤甲基化表型（G-CIMP）的功能和调节

• 批准号: 256447356
• 负责人: Dr. Maria Stella Carro
• 金额: --
• 依托单位: Klinik für Neurochirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/256447356?language=en
• 关键词: Function; regulation; glioma; methylator; phenotype

Glioblastoma multiforme (GBM) is the most common and malignant brain tumor in adults with a median survival of one year. In recent years, many studies have provided important contributions to the characterization of molecular subtypes of gliomas with the identification of gene signatures associated with clinical outcome and survival. In particular, the mesenchymal signature appears to characterize GBM with the worst outcome. Cancer-specific DNA methylation changes are hallmarks of human cancers. Promoter CpG island hypermethylation generally results in transcriptional silencing of the associated genes. A recent study by the Cancer Genome Atlas group (http://cancergenome.nih.gov/) revealed the existence of a glioma methylator phenotype (G-CIMP) in a subset of GBMs. These GBMs are characterized by hypermethylation at a large number of foci, belong to the proneural subgroup and are associated with IDH1 somatic mutations. Recently, we have identified the calcium dependent phospholipid binding protein Annexin2 (ANXA2) as a putative regulator of the mesenchymal signature. In this proposal we are going to study the signaling mechanism by which ANXA2 regulates the mesenchymal signature and affects survival in GBM. We hypothesize that ANXA2 could activate the mesenchymal signature by either activating a signaling pathway leading to activation of specific transcriptional regulators or through demethylation of mesenchymal genes. In addition, we plan to identify and characterize additional methylated events which could be important in survival. Finally, we will analyze promoter regions of G-CIMP genes to identify common cis-modulatory motifs that could indicate the existence of common binding factor sites. According to our model, such common modules of transcription factors binding, in combination with epigenetic or genetic changes specifically occurring in proneural tumors (i.e.IDH1 mutation), could play a role in the establishment of the methylation pattern in this tumor subclass.

多形性胶质母细胞瘤（GBM）是成人中最常见的恶性脑肿瘤，中位生存期为一年。近年来，许多研究为胶质瘤分子亚型的表征提供了重要贡献，并鉴定了与临床结局和生存相关的基因特征。特别地，间充质特征似乎表征具有最差结果的GBM。癌症特异性DNA甲基化变化是人类癌症的标志。启动子CpG岛超甲基化通常导致相关基因的转录沉默。癌症基因组图谱组（http：//cancergenome.nih.gov/）最近的一项研究揭示了GBM亚组中存在胶质瘤甲基化表型（G-CIMP）。这些GBM的特征在于在大量病灶处的超甲基化，属于前神经亚组，并且与IDH 1体细胞突变相关。最近，我们已经确定钙依赖性磷脂结合蛋白膜联蛋白2（ANXA 2）作为间充质签名的假定调节剂。在这个提案中，我们将研究ANXA 2调节间充质签名并影响GBM存活的信号传导机制。我们假设ANXA 2可以通过激活导致特定转录调节因子激活的信号通路或通过间充质基因的去甲基化来激活间充质签名。此外，我们计划确定和表征其他甲基化事件，这可能是重要的生存。最后，我们将分析G-CIMP基因的启动子区域，以确定共同的顺式调节基序，可以表明共同的结合因子位点的存在。根据我们的模型，这些共同的转录因子结合模块，结合特异性发生在前神经肿瘤中的表观遗传或遗传变化（即IDH 1突变），可能在该肿瘤亚类中甲基化模式的建立中发挥作用。