DNA methylation in medulloblastoma
Brain tumors are the leading cause of death from cancer in children under the age of 15 years. Medulloblastoma, the most common pediatric brain tumor, continues to have 5-year overall survival rates of 60%. Furthermore disease and treatment related morbidity is a major problem. Developing disease risk assessment tools for targeting current therapeutics is vital. Developing novel therapies that are less toxic is also crucial.
Our hypothesis is that DNA methylation suppreses expression of tumor supressor genes in medulloblastoma and that these methylation marks can be used as diagnostic tools. I propose to investigate the role of epigenetic gene silencing in medulloblastoma, particularly with respect to developing novel biomarkers for tumor risk assessment. Epigenetic therapy is a promising new approach to cancer therapy. The genomic implications of such therapy need to be explored. In Specific Aim 1, I will examine the network of genes re-expressed by inhibition of DNA methylation in medulloblastoma using microarray gene expression techniques. Given the heterogeneity of clinical outcomes the gene expression profiles of silenced genes may help predict disease behavior. In this context I will examine the expression of these genes in medulloblastoma patients and correlate them to clinical parameters in Specific Aim 2. Many genes are silenced by DNA methylation. These methylation marks can predict tumor responsiveness to therapy. In Specific Aim 3, I propose to detect and categorize methylation marks in medulloblastoma and test their ability to predict tumor behavior. We expect to develop and validate a set of biomarkers in this study that can subsequently be tested in a large clinical study.