Grant: CIHR Fellowship

High-grade astrocytomas (HGAs) are aggressive brain tumors that have limited treatment options and very high mortality rates. One third of these tumors contain a particular genetic mutation in a protein called histone H3F3A which regulates the development and growth of many tissues by controlling the function and integrity of DNA molecules. These specific mutations occur at a particular position whereby the amino acid at position 34 changes from a Glycine to an Arginine or a Valine in a specific area of the brain. Surprisingly, in Giant cell tumor of the bone (GCTB), a mutation is observed at the same position (G34) but the genetic mutation causes it to change into a Tryptophan or a Leucine. It is therefore very interesting that this same gene can be mutated specifically into 2 different amino acids in 2 distinct types of cancer. So, my project will study why these particular mutations are specific to these different types of tissue (brain and bone) and what are the molecular components implicated in the tumorigenesis of these 2 cancers by introducing these mutations in cancer precursor cells using a genome editing technology called the CRISPR-Cas9 system. Then, these mutated cells will put in a differentiation media to differentiate them into specific cell types (Astrocytes and Chondrocytes). Level of differentiation will be compared between each other for all G34 mutations (R/V vs W/L). Finally, the DNA and RNA contents of every G34 mutated-hMSC before and after differentiation will be compare to patient tumor samples using Next-Generation Sequencing technologies (ChIP-seq/RNA-seq). This research will hopefully provide insights on the molecular and genetic factors that influence the tumorigenesis of pediatric brain and bone cancers in order to find new therapeutic targets and improve current personalized therapies that will increase the survival and the quality of life of Canadians and also world-wide pediatric patients.