Poster #104 - Minh Nguyen

Large-scale Phylogenetic Analysis of Intra-tumor Genetic Heterogeneity Dynamics in Pediatric Brain and CNS Tumor

Minh A. Nguyen (1) Pablo G. Cámara, PhD (1) (1) Department of Genetics, Perelman School of Medicine, University of Pennsylvania

Brain and central nervous system (CNS) tumors are the second most common cancers in children and adolescents and remain the leading cause of disease-related death in these populations. Despite their clinical impact, therapeutic development has been limited by the tumor heterogeneity, and the clonal architecture and evolutionary dynamics of pediatric brain cancers remain poorly characterized. Addressing this knowledge gap is critical, as intra-tumor heterogeneity, driven by genetically distinct subclones, shapes disease progression and treatment resistance. To investigate clonal evolution at scale, we analyzed whole-genome sequencing data from 1,738 tumors across 68 subtypes in 1,479 patients from the Children's Brain Tumor Network. We reconstructed clonal composition and phylogenetic relationships and quantified topological dissimilarity between trees using a regularized Gromov-Hausdorff distance. Phylogenetic structure was significantly associated with mutational burden, mutational signatures, cancer classification, and survival. In longitudinal analyses, survival remained significantly associated after adjusting for mutational burden, tumor subtype and location. In contrast, in primary tumors, mutational signatures remained significant after adjusting for mutation count, tumor classification, location and purity, while survival lost significance. Comparisons of matched longitudinal and primary tumor phylogenetic trees revealed that deceased patients and those with recurrent or metastatic disease exhibited significantly greater divergence, indicating that primary tumors are less predictive of complete clonal trajectories in poor-outcome cases. These findings suggest that pediatric brain tumor evolution is shaped by cancer type and mutational processes, and that patients with adverse outcomes follow distinct evolutionary trajectories independent of subtype. Collectively, this study provides the first large-scale view of clonal evolution in pediatric brain tumors and underscores the value of genetic clonal dynamics as a framework for understanding tumor etiology and progression. Ongoing work investigates the timing and order of driver events and mutational processes and their roles in shaping clonal trajectories.