Characterizing Novel Rearrangements in Diffuse Intrinsic Pontine Glioma
Diffuse intrinsic pontine gliomas (DIPG) are devastating childhood brain tumors. There are no known curative treatments for DIPG. DIPGs arise in a delicate part of the brain known as the brainstem, rendering them un-resectable. Even biopsy of the tumors has been historically avoided due to the critical function of the brainstem. The lack of biopsy samples has greatly hampered understanding of the biology of the tumors.
Our group led the first multi-institute clinical trial (DIPG-BATs) to incorporate diagnostic biopsies of children with DIPG with molecular stratification of treatment approaches. We have performed whole-genome sequencing of these samples and uncovered novel genomic rearrangements. One such rearrangement results in a tandem duplication in close proximity to a gene that is commonly associated with cancer: MYC.
Yohanna Georgis proposes to characterize the functional consequence of this genomic alteration. She will test the hypothesis that this rearrangement activates the MYC oncogene in DIPG. To achieve this, Yohanna will clone the DNA sequence and determine whether this is able to ‘turn on’ the MYC gene. She will also test a number of cell lines that have been generated from patient DIPG samples to determine if any of them harbor the rearrangement. She will then determine whether the lines are dependent on the DNA sequence for ongoing growth. To achieve this, Yohanna will use the CRISPR-cas9 system to disrupt the rearrangement to determine whether this is sufficient to kill cells.