EPCO-52. INVESTIGATING EGFR CONTAINING EXTRACHROMOSOMAL DNA DYNAMICS IN GBM

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Abstract The epidermal growth factor receptor (EGFR) is the most frequently altered gene in GBM, with EGFR amplification occurring in approximately 40% of all glioblastomas, half of which exhibit the EGFRvIII deletion variant. EGFR amplification often occurs through the formation of extrachromosomal DNA (ecDNA), where EGFR typically co-amplifies with upstream enhancers. ecDNA is commonly found in a wide range of cancer types, particularly Glioblastoma (GBM), but is rare in normal cells. The uneven segregation of ecDNAs results in oncogene copy number variations in subclones, producing highly heterogeneous tumor cells and providing a selective advantage to cancer cells in response to changing environmental conditions. Meanwhile, ecDNAs keep evolving through fusion, deletion, or integration of new fragments, resulting in alterations to their structure and sequence. Some ecDNAs can reintegrate into chromosomal DNA, disrupting the integrity of chromosomal genes or rewiring chromosomal gene expression via ecDNA resident enhancers. However, the dynamics of EGFR-containing ecDNA (ecEGFR) have not been thoroughly investigated across primary and recurrent GBM. In this study, we profiled 47 glioblastoma specimens (both primary and recurrent) using a multi-omic approach, including WGS, RNA-seq, and ATAC-seq, identifying ecDNA in 14 samples, 10 of which carried EGFR. EGFR deletions were observed in 4 ecEGFR-positive samples, with 2 being the vIII variant. Interestingly, EGFR deletions predominantly occurred in the primary GBM. These ecEGFR samples exhibited significantly high EGFR copy number, gene expression, and chromatin accessibility. Additionally, there were samples with ecEGFR in the primary tumor but not in the recurrent tumor, or ecEGFR appears only in recurrent tumor. One patient showed an ecEGFR deletion in the primary tumor, while the recurrent tumor exhibited wild type ecEGFR.