The Role of DNA Methylation in Pediatric Cancer

While much success in the treatment of pediatric cancers has been obtained over the past 20 years by optimizing the use of previously discovered chemotherapies, new agents are desperately needed to cure those patients who do not respond to current therapy. DNA mutations and structural abnormalities in chromosomes contribute to cancer formation by improperly regulating genes in the cell. Another mechanism by which genes become misregulated in cancer is through aberrant DNA methylation. DNA methylation is a normal process used by cells to mark the DNA itself in such a way as to allow information to be passed on to successive generations of cells, and it is essential for normal development. Cancer cells can exploit this mechanism to silence genes important for preventing tumor formation. While this phenomenon has been extensively studied in adult cancers, there is a relative dearth of information about how abnormal DNA methylation contributes to the formation of pediatric cancer. Given the relatively short time frame in which pediatric cancers develop, aberrant DNA methylation may play an important role in pediatric disease. Using a novel assay we have developed, we will study how DNA methylation contributes to the formation of medulloblastoma, the most common pediatric malignant brain tumor. We will use mouse models of the disease, as well as actual tissue samples from patients, to discover new targets for therapy and understand how drug resistance develops. Our long-term goals are to improve cure rates for this disease and obtain knowledge to understand pediatric cancers in general.