Comprehensive Analysis of the Molecular Underpinnings of Pediatric Glioma

Tumors arising in the central nervous system (CNS) are the largest group of solid tumors affecting children. Of these CNS tumors, gliomas are the most prevalent. Currently gliomas are histologically segregated into two umbrella categories: low-grade glioma (grades 1 and 2, pLGG) and high-grade glioma (grade 3 and 4, pHGG). pLGG are the most frequently diagnosed pediatric glioma. Although overall survival of these tumors is robust, extensive clinical heterogeneity exists, specifically as it pertains to the patient's long-term prognosis. Molecular studies over the past decade have identified that pLGG frequently harbor genetic alterations in the RAS/MAPK pathway, although a comprehensive molecular landscape of the disease has yet to be completed. To address this, we characterized a population-based cohort of >1,000 pLGG. We discovered that RAS/MAPK pathway dysregulation was universal in pLGG. Further, pLGG could be clinically classified based on their underlying alteration type: rearrangement or SNV. Further sub-classification stratified pLGG into clinical risk groups, highlighting patients at risk for a worsened prognosis. Diffuse intrinsic pontine glioma (DIPG) is a subtype of pediatric glioma that arises in the pons of children. DIPG prognosis is dismal, with a median survival of 10 months. Previous sequencing efforts identified frequent p.K27M mutations in Histone H3 which resulted in a global loss of K27 (di/tri)-methylation. Here, we collected tissue from DIPG patients from multiple sites of tumor dissemination and the primary pontine lesion for multi-omics analysis. We uncovered homogeneity of tumor defining alterations, including H3 p.K27M, but heterogeneity of many accessory alterations. Clonal evolution modelling uncovered that H3 p.K27M was the most frequent initiating event in DIPG, but universally required an obligate molecular event, most often a TP53 mutation, to promote tumorigenesis. In an effort to understand the molecular interplay of DIPG evolution, we developed a bioinformatics approach that integrated methylation and gene expression changes into our evolutionary model. Doing so revealed unique clonal pathway dysregulation, including up-regulation of cell migration and angiogenesis in highly invasive clones. Collectively, our analysis revealed several key tumorigenic properties of DIPG and provides a deeper understanding of DIPG pathogenesis.

Department dc:contributor.department

Laboratory Medicine and Pathobiology

Year dc:date.issued

2021

Author dc:creator

• Ryall, Scott Thomas

Advisor dc:contributor.advisor

• Hawkins, Cynthia

• BRAF
• Clonal Evolution
• DIPG
• Glioma
• pLGG
• Risk Stratification

Handle dc:identifier.uri

http://hdl.handle.net/1807/104944

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/104944