100. Identification of unique subtypes of pediatric high-grade glioma by comparative tumor transcriptomics

Aly Abdelkareem

Gina Mawla

Dr. Gina Mawla is a Postdoctoral Fellow in the Department of Molecular, Cell and Developmental Biology in Dr. Olena Vaske’s lab at the University of California, Santa Cruz. She is a member of the Treehouse Childhood Cancer Initiative at the UCSC Genomics Institute, founded and led by Dr. Vaske. Dr. Mawla’s research focuses on leveraging and applying information gained from genomic and transcriptomic sequencing techniques to inform the specific diagnoses and treatment plans of patients afflicted by rare pediatric diseases. She is currently developing novel experimental and high-throughput analysis approaches to discover and functionally characterize new druggable molecular targets of pediatric high-grade glioma. Dr. Mawla holds a PhD in Biology from the Massachusetts Institute of Technology. She is a recipient of the Institutional Research and Academic Career Development Award (IRACDA), which recognizes her interest in and commitment to teaching and pedagogy in addition to research. ​


Gina Mawlaa, Geoff Lylea, Ellen Kepharta, Katrina Learneda, Holly Bealea, Joshua Goldfordb, Olena Vaskea

aUniversity of California, Santa Cruz, Santa Cruz, CA, USA; bMassachusetts Institute of Technology, Cambridge, MA, USA

Pediatric high-grade glioma (pHGG) is a devastating and poorly understood cancer driven by numerous genetic and epigenetic mechanisms. Here, we use numerous bioinformatics approaches to analyze transcriptomic data of 1,543 pediatric brain tumor specimens from the UCSC Treehouse Childhood Cancer Initiative (Treehouse) and Open Pediatric Brain Tumor Atlas (OpenPBTA) to subtype pHGG patients. We find that approximately half (49.5%) of pHGG tumors from OpenPBTA can be partitioned into three subgroups defined by high outlier-level expression either of: mitochondrially-encoded 12S and 16S rRNAs; genes enriched in the HSF1-mediated heat shock response and activation pathways; or six C/D box snoRNA (SNORD) genes originating from the paternally-expressed SNORD116 locus involved in Prader-Willi syndrome, a complex neurodevelopmental disorder. Interestingly, the same set of HSF1-dependent pathway genes is also significantly upregulated in a subset (~11%) of pHGG tumors from Treehouse, validating this finding in two independent compendia with different transcript isolation strategies. Our work discovers distinct classes of tumors with outlier-level expression of genes with previously unknown roles in pHGG and provides a framework for subtyping tumors by comparative transcriptomics that is adaptable to any cancer type. We are currently investigating the molecular roles of HSF1-response genes and the imprinted SNORD116 gene cluster in pHGG. Our ongoing research into the biomolecular signatures and mechanisms of the three major tumor classes of pHGG as defined in our study will contribute to a greater understanding of pHGG disease manifestation and progression, and will inform strategies of tailored therapeutic interventions for children with this fatal disease.