Grant: CIHR Fellowship

On average, 500 Canadians are diagnosed with cancer every day and 27 of these new cases are brain tumor. Astrocytomas are the most common primary brain tumors and are graded into four groups (I-IV) based on their degrees of severity by the World Health Organization (WHO). Glioblastoma multiforme (GBM), the highest graded Astrocytoma (WHO grade IV), is the most common and lethal form of primary brain tumor. Despite recent advances in treatment, including surgery, radiation therapy and chemotherapy, the outcome remains quite poor, with a median survival time of 12-15 months after diagnosis. Recently, our laboratory identified mutations in an important gene known as histone 3.3 in a significant proportion of children (40%) diagnosed with glioblastoma. This histone gene is involved in regulating the development and growth of many body tissues, including the brain. Mutations in H3.3 may partly explain why children with this deadly cancer remain unresponsive to traditional treatments. We are now in a position to take advantage of our recent breakthrough discovery to identify other genes and pathways that collaborate with H3.3 mutations to drive tumor development (tumorigenesis) in pediatric GBM. To this end, we will use 100 matched tumor - normal pairs for next-generation sequencing (exome and RNA sequencing). Mutations identified will be confirmed by Sanger sequencing and their effects at the protein level will be evaluated by immunohistochemistry and Western blot analyses. I believe that the candidate genes identified in this study, along with H3.3 mutations, will serve as reliable, sensitive and effective diagnostic tools in classifying patients based on their genetic makeup and provide treatments tailored to their tumor biology. Personalized approaches and targeted therapies will not only benefit Canadians but also patients worldwide by reducing cost of treatment, minimizing side effects, decreasing mortality, and improving quality of life and survival.