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

多形性胶质母细胞瘤(GBM)是成人最常见的恶性脑肿瘤，中位生存期为一年。近年来，许多研究通过识别与临床结果和生存相关的基因信号，为确定胶质瘤的分子亚型提供了重要的贡献。尤其是，间质信号似乎是预后最差的GBM的特征。癌症特有的DNA甲基化变化是人类癌症的标志。启动子CpG岛超甲基化通常会导致相关基因的转录沉默。癌症基因组图谱小组(http://cancergenome.nih.gov/))最近的一项研究显示，在胶质瘤甲基化表型(G-CIMP)的一个子集的GBM。这些基底膜的特点是大量病灶的高度甲基化，属于原神经亚群，与IDH1体细胞突变有关。最近，我们发现钙依赖的磷脂结合蛋白Annexin2(ANXA2)可能是间充质信号的调节因子。在这个方案中，我们将研究ANXA2调节间充质信号并影响GBM存活的信号机制。我们假设ANXA2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去甲基化间充质基因来激活间充质信号。此外，我们计划识别和描述其他甲基化事件，这些事件可能对生存很重要。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控基序，这些基序可能表明存在共同的结合因子位点。根据我们的模型，这些共同的转录因子结合模块，结合神经前肿瘤特有的表观遗传学或基因变化(即IDH1突变)，可能在这一肿瘤亚类中甲基化模式的建立中发挥作用。

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.