Noorani Imran, Haughey Magnus, Luebeck Jens, Rowan Andrew, Grönroos Eva, Terenzi Francesco, Wong Ivy Tsz-Lo, Pradella Davide, Lisi Marta, Kittel Jeanette, Sharma Natasha, Bailey Chris, Weeden Clare E, Bell Donald M, Joo Eric, Barbè Vittorio, Jones Matthew G, Hung King L, Nye Emma L, Green Mary, Meader Lucy, Norton Emma J, Fabian Mark, Kanu Nnennaya, Jamal-Hanjani Mariam, Santarius Thomas, Ventura Andrea, Nicoll James A R, Boche Delphine, Chang Howard Y, Bafna Vineet, Huang Weini, Mischel Paul S, Swanton Charles, Werner Benjamin
Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, United Kingdom.
Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
Cancer Discov. 2025 Sep 8:OF1-OF18. doi: 10.1158/2159-8290.CD-24-1555.
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.
We study spatial patterns of ecDNA-amplified oncogenes and their evolutionary properties in human GBM, revealing an ecDNA landscape and ecDNA oncogene-specific evolutionary histories. ecDNA accumulation can precede clonal expansion, facilitating the emergence of EGFR oncogenic variants, reframing our interpretation of genomic data in a large subset of GBMs. See related article by Korsah et al., p. XX.
在染色体外DNA（ecDNA）上扩增的致癌基因导致多种癌症产生治疗抗性并预后不良。目前，人们对ecDNA的时空进化仍知之甚少。在本研究中，我们将计算模型与94例未经治疗的人类胶质母细胞瘤（GBM）样本相结合，以研究ecDNA的时空进化。我们观察到ecDNA空间异质性的致癌基因特异性模式，这源于随机的ecDNA分离和不同的适应性优势。与血小板衍生生长因子受体A（PDGFRA）-ecDNA不同，表皮生长因子受体（EGFR）-ecDNA通常在克隆扩增之前积累，赋予强大的适应性优势并达到高丰度。与此相符的是，我们在基因工程小鼠神经干细胞的体内观察到肿瘤前ecDNA的积累。变异型和野生型EGFR-ecDNA经常在GBM中共存。那些变异型EGFR-ecDNA，最常见的是EGFRvIII-ecDNA，总是源自预先存在的野生型EGFR-ecDNA，出现较早，并达到高丰度。我们的结果表明，ecDNA致癌组成决定了独特的进化轨迹之路。诸如ecDNA克隆性和异质性等新概念需要对大量GBM中的基因组数据进行精细的进化解释。
我们研究了人类GBM中ecDNA扩增致癌基因的空间模式及其进化特性，揭示了ecDNA格局和ecDNA致癌基因特异性进化史。ecDNA积累可先于克隆扩增，促进EGFR致癌变异的出现，重新构建了我们对大量GBM中基因组数据的解释。见Korsah等人的相关文章，第XX页。
