Unlabelled: Oncogene amplification on extrachromosomal DNA (ecDNA) is strongly associated with treatment resistance and shorter survival for patients with cancer, including patients with glioblastoma. The non-chromosomal inheritance of ecDNA during cell division is a major contributor to intratumoral genetic heterogeneity. At present, the spatial dynamics of ecDNA, and the impact on tumor evolutionary trajectories, are not well understood. Here, we investigate the spatial-temporal evolution of ecDNA and its clinical impact by analyzing tumor samples from 94 treatment-naive human -wildtype glioblastoma patients. We developed a spatial-temporal computational model of ecDNA positive tumors ('SPECIES') that integrates whole-genome sequencing, multi-region DNA FISH, and nascent RNAscope, to provide unique insight into the spatial dynamics of ecDNA evolution. Random segregation in combination with positive selection of ecDNAs induce large, predictable spatial patterns of cell-to-cell ecDNA copy number variation that are highly dependent on the oncogene encoded on the circular DNA. ecDNAs often reach high mean copy number (mean of 50 copies per tumor cell), are under strong positive selection (mean selection coefficient, > 2) and do not co-amplify other oncogenes on the same ecDNA particles. In contrast, ecDNAs have lower mean copy number (mean of 15 copies per cell), are under weaker positive selection and frequently co-amplify other oncogenes on the same ecDNA. Evolutionary modeling suggests that ecDNAs often accumulate prior to clonal expansion. structural variants, including and c-terminal deletions are under strong positive selection, are found exclusively on ecDNA, and are intermixed with wild-type ecDNAs. Simulations show ecDNA likely arises after ecDNA formation in a cell with high wild-type copy number (> 10) before the onset of the most recent clonal expansion. This remains true even in cases of co-selection and co-amplification of multiple oncogenic ecDNA species in a subset of patients. Overall, our results suggest a potential time window in which early ecDNA detection may provide an opportunity for more effective intervention.
Highlights: ecDNA is the most common mechanism of focal oncogene amplification in wt glioblastoma. and its variants on ecDNA are particularly potent, likely arising early in tumor development, providing a strong oncogenic stimulus to drive tumorigenesis. Wild-type and variant ecDNA heteroplasmy (co-occurrence) is common with vIII or c-terminal deletions being derived from wild-type ecDNA prior to the most recent clonal expansion. Tumors with ecDNA amplified versus exhibit different evolutionary trajectories. SPECIES model can infer spatial evolutionary dynamics of ecDNA in cancer.A delay between ecDNA accumulation and subsequent oncogenic mutation may give a therapeutic window for early intervention.
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http://dx.doi.org/10.1101/2024.10.22.619657 | DOI Listing |
Transl Cancer Res
November 2024
Medical Oncology Centre, Saalfeld, Germany.
Non-small cell lung cancer (NSCLC) represents over 80% of lung cancer cases and has a high mortality worldwide, however, targeting common epidermal growth-factor receptor (EGFR) alterations (i.e., del19, L858R) has provided a paradigm shift in the treatment of NSCLC.
View Article and Find Full Text PDFNature
December 2024
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Focal gene amplifications are among the most common cancer-associated mutations but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1 Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs) in a spatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures.
View Article and Find Full Text PDFIntractable Rare Dis Res
November 2024
Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, Hainan, China.
Biomedicines
November 2024
Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia.
: Sepsis is characterized by a dysregulated immune response to infection and is associated with high lethality. Extracellular DNA (ecDNA) has drawn significant interest as a damage-associated molecular pattern because of its potential involvement in the pathophysiology of sepsis. : In this study, we examined the ecDNA concentration in 27 adult patients admitted to the intensive care unit.
View Article and Find Full Text PDFComput Struct Biotechnol J
December 2024
Medical Research Center, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Circular extrachromosomal DNA (ecDNA) plays a crucial role in the onset, progression, and evolution of many types of cancers, with dysregulated gene expression driven by ecDNA as a key mechanism. Although database resources for ecDNA are now available, a sophisticated web application dedicated to ecDNA gene analysis remains absent. Therefore, we developed ecDNA gene analyzer (ECGA).
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