Extrachromosomal DNA–Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma
Menée à l'aide notamment de modèles murins génétiquement modifiés et d'échantillons tumoraux fixés au formaldéhyde et inclus en paraffine après prélèvement sur des patients atteints d'un glioblastome, cette étude examine le rôle de l'ADN extra-chromosomique dans l'hétérogénéité spatiale et l'évolution de la tumeur
Oncogenes amplified on extrachromosomal DNA (ecDNA) contribute to treatment resistance and poor survival across cancers. Currently, the spatiotemporal evolution of ecDNA remains poorly understood. In this study, we integrate computational modeling with samples from 94 treatment-naive human glioblastomas (GBM) to investigate the spatiotemporal evolution of ecDNA. We observe oncogene-specific patterns of ecDNA spatial heterogeneity, emerging from random ecDNA segregation and differing fitness advantages. Unlike PDGFRA-ecDNAs, EGFR-ecDNAs often accumulate prior to clonal expansions, conferring strong fitness advantages and reaching high abundances. In corroboration, we observe pretumor ecDNA accumulation in vivo in genetically engineered mouse neural stem cells. Variant and wild-type EGFR-ecDNAs often coexist in GBM. Those variant EGFR-ecDNAs, most commonly EGFRvIII-ecDNA, always derive from preexisting wild-type EGFR-ecDNAs, occur early, and reach high abundance. Our results suggest that the ecDNA oncogenic makeup determines unique evolutionary trajectories. New concepts such as ecDNA clonality and heteroplasmy require a refined evolutionary interpretation of genomic data in a large subset of GBMs.
Cancer Discovery , article en libre accès, 2025