Discordant inheritance of chromosomal and extrachromosomal DNA elements contribute to dynamic disease evolution in glioblastoma

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Somatic evolution in glioblastoma (GBM) is a dynamic process favoring clonal architecture beneficial to tumor growth. Oncogene amplification in extra-chromosomal DNA (ecDNA) is frequent in GBMs. In contrast to somatic chromosomal abnormalities, ecDNA amplification results in highly variable copy number per cell, unequal distribution into daughter cells, and rapid copy number regulation to favor tumor cell fitness in response to environmental changes. Therapeutic interventions and the changes in the environment during the generation of patient-derived models represent selective pressures considered in this study. We performed exome and low pass whole genome sequencing to study: (A) 12 newly diagnosed GBM biopsies and 1 matched recurrent tumor, representing the most frequent genomic abnormalities, the derived neurosphere culture, and orthotopic xenograft trios; (B) 58 matching pairs of primary-recurrent gliomas. The presence of ecDNA was predicted from DNA copy number analysis and further investigated by FISH in tissue samples and metaphase spreads. We found that 100% of homozygous deletions and somatic single nucleotide variants (sSNVs) affecting GBM driver genes in the tumor samples were propagated to the neurospheres and xenografts. Focal amplification of 1 to 3 oncogenes/tumor was found in ecDNA for 7 of the 13 cases. CDK4, MDM2, EGFR, and PDGFRA ecDNA amplifications were maintained from the tumor to all models. Frequency of ecDNA MYC amplification was low in 2 newly diagnosed GBMs (0.5 and 2% cells), increasing to 100% in the recurrent tumor for one case, and in all models for both cases. Frequency of MET ecDNA remarkably decreased in culture and was recovered in the xenografts. For the primary-recurrent glioma pairs, receptor-tyrosine kinase amplification in ecDNAs was frequently retained after recurrence, regardless of treatment, while ecDNA bearing MYC amplification emerged in the recurrent tumor. Our results highlight the importance of ecDNA in glioma evolution, with implications for clinical and pre-clinical studies.





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