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

• Applicant: Dr. Maria Stella Carro
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 256447356

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.

• DFG Programme: Research Grants