Functional analysis of epigenetically regulated genes in brain tumors

Coordinator:    Dr. Andreas Waha
Institution: Institut für Neuropathologie, Medizinische Fakultät der Universität Bonn
The inactivation of genes by DNA methylation is a frequent event in tumors and affects genes coding various cellular functions. The major goal of this subproject is to characterize the functional impact of genes silenced by specific hypermethylation in brain tumors. This goal will be approached by two strategies. Verified candidate genes, uncovered by previous CpG island microarray analyses will be investigated in vitro to understand their functional role for brain cancer cells. Using genome wide analyses of DNA methylation in primary brain tumor samples, our suproject has already identified more than 200 candidate genes involved in relevant signalling pathways e.g. cell-cell and cell-matrix interaction, the transmission of growth signals and the regulation of cell death. In addition, we aim to use recent in vitro and in vivo systems to unmask epigenetically silenced genes relevant for major clinical complications of brain tumors like invasive growth, angiogenesis and chemoresistance. Aberrations in the methylation of cancer relevant genes have been associated with all established hallmarks of cancer. The focussed screen for novel differentially methylated genes in selected brain tumor models will provide further information on the pathology of brain tumors. The combination of comprehensive information on DNA methylation and structural alterations, targeted by state of the art sequencing technology also provided in this consortium, will lead to a significant synergistic effect accelerating the discovery of novel pathways involved in the molecular pathogenesis of gliomas. The joint effort of these complementary investigations will therefore result in a better understanding of the molecular bases of these neoplasms and the discovery of novel targets for efficient treatment of brain tumor patients.
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