Data from Extrachromosomal DNA–Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma

作者：Imran Noorani, Magnus Haughey, Jens Luebeck, Andrew Rowan, Eva Grönroos, Francesco Terenzi, Ivy Tsz-Lo Wong, Davide Pradella, Marta Lisi, Jeanette Kittel, Natasha Sharma, Chris Bailey, Clare E. Weeden, Donald M. Bell, Eric Joo, Vittorio Barbè, Matthew G. Jones, King L. Hung, Emma Nye, Mary Green, Lucy Meader, Emma Norton, Mark Fabian, Nnennaya Kanu, Mariam Jamal‐Hanjani, Thomas Santarius, Andrea Ventura, James A. R. Nicoll, Delphine Boche, Howard Y. Chang, Vineet Bafna, Weini Huang, Paul S. Mischel, Charles Swanton, Benjamin Werner · 年份：2025 · DOI：10.1158/2159-8290.c.8072552 · 被引用次数：1 · 研究领域：Cancer Genomics and Diagnostics

<div>AbstractOncogenes 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.Significance:We study spatial patterns of ecDNA-amplified oncogenes and their evolutionary properties in ...