Finding new treatment options for pediatric high-grade gliomas is important because most children with glioblastomas die within a year of being diagnosed. Despite over 30 years of clinical research, little progress has been made, suggesting that a need to better understand the basic processes by which these tumors form to find more effective strategies for treatment. The team expects to experimentally confirm that localized p53 hypermutability is a true phenomenon and demonstrate that this mechanism is involved in gliomagenesis. They will also provide the allelic spectrum of p53 as well as an accurate, cost-effective method for sequencing a large pool of variable DNA specimens – both of which will be widely valuable. The results of this work have the potential to provide broader understanding of an important mechanism of tumorigenesis and, more specifically, significant advances in understanding malignant transformation of pediatric highgrade glioma, which can lead to advancements in the treatment of these young people.
Using next-generation DNA sequencing technology, Drs. Druley and Mitra have successfully designed and implemented a method to accurately determine the identity and frequency of rare gene variants from a pool of random DNA samples. This method requires a fraction of the time and 100-fold less cost than previously associated with such an endeavor. With this method, the investigators will be able to 1) screen populations of affected individuals and identify rare gene variants that may contribute to disease, 2) perform large-scale population surveys of random individuals to determine the true global frequency of disease-causing gene variants, and 3) following analysis of many more samples, determine if p53 is truly hypermutable and whether such a mechanism contributes to pediatric brain cancer formation.