Investigating the impact of glioma-associated germline risk alleles on neurodevelopmental trajectories

PROJECT SUMMARY Targeting the molecular abnormalities driving malignant glioma has proven challenging, due in large part to the inherent heterogeneity and complexity of the fully transformed cancer state. An improved understanding of the molecular and cellular events preceding glioma formation has the potential to elucidate innovative and practice- altering patient management paradigms. This proposal seeks to clarify this understudied research area, focusing on the concept of preneoplastic priming in glioma cell-of-origin pools. Our studies focus on glioma-associated risk SNPs (GASNPs), which have been shown in epidemiological studies to increase the likelihood of glioma acquisition but not invariably cause disease. GASNPs tend to localize to enhancer domains in proximity to established cancer-associated genes (e.g., TP53), suggesting that their presence fundamentally alters epigenomic landscapes and phenotypically relevant gene expression. We recently demonstrated in human induced pluripotent stem cell (iPSC)-derived isogenic organoids that two GASNPs, rs7572263 and rs78378222, impair normal neuronal differentiation, arresting cells in the neural progenitor stage. Intriguingly, this finding echoes earlier work by our group, implicating partially differentiated neural progenitors as cells of origin for major glioma subclasses. Accordingly, we hypothesize that these GASNPs fundamentally alter epigenomic landscapes and transcriptional profiles in developmentally relevant contexts, expanding and neoplastically priming distinct precursor cell pools. In this proposal, we will leverage single cell and bulk profiling approaches in recently optimized iPSC and knock-in mouse reagents to interrogate the epigenetic and transcriptional mechanisms by which rs7572263 and rs78378222 dysregulate neurodevelopmental trajectories and promote gliomagenesis. If successful, our work will lay the foundation for more comprehensive studies moving forward, conducted by our team as well as other groups, and reveal tangible opportunities for improved treatment and management strategies for an intractable and deadly disease.