Ancestral Genetic Homogeneity in Preclinical Models May Shape Outcome Differences in Pediatric Brain Cancer

The influence of genetic ancestry on cancer development and treatment response is underappreciated within pediatric neuro-oncology. Pediatric brain tumors (PBT) comprise the deadliest malignancies among childhood cancers. Poorer prognoses are accentuated in minority populations and remain skewed despite attempts to address social determinants of health and clinical trial underrepresentation. Ancestral differences in tumor biology and pharmacogenomics may contribute to outcome discrepancies. As such, we sought to review the role of genetic ancestry in PBT biology and treatment response and investigate whether foundational preclinical models adequately reflect ancestral heterogeneity. Population-linked genetic events are correlated with biological tumor differences but remain nascently explored. Likewise, there are indications that ancestral variations may influence treatment outcomes. Yet, despite data supporting response differences between ancestries in non-brain tumor populations, few therapeutics have been pharmacogenetically tested. Additionally, assessment of ancestral identity of brain cancer cell lines demonstrated lack of genetic ancestral heterogeneity, with European and Asian overrepresentation. Hence, therapeutic insights are being constructed with a preselected population lacking genetic diversity, decreasing the breadth of clinical translation and further exacerbating health disparities. This review proposes steps to address this gap and promote ancestral heterogeneity in treatment development within pediatric neuro-oncology.