Biology subjects

Sun, E. G.

Publications and source records attributed to Sun, E. G..

2 recordsLinked to original sources

bioRxiv2026

Evolution of oncogene amplification across 86,000 cancer cell genomes

High-level copy-number (CN) amplification (HLAMP) is a major mechanism of oncogene activation in human cancer. Despite progress in therapeutically targeting amplified oncogenes, the processes underlying amplicon evolution remain incompletely understood, leaving critical knowledge gaps in their etiology and mechanisms of therapeutic response. To address this, we analyzed the evolutionary trajectories of HLAMPs using single-cell whole-genome sequencing data from 86,239 cancer cells across 93 patients and 9 experimental systems. We found that cell-to-cell CN variability provides a quantifiable readout of HLAMP mechanism, clearly distinguishing extrachromosomal circular DNA (ecDNA) from intrachromosomal amplification (ICamp) through characteristic CN distributions that reflect distinct modes of segregation and correspond to clonal architecture. Notably, ICamp events frequently showed multiple amplitude peaks specific to subclones, indicating punctuated shifts in oncogene dosage through numeric or structural modulatory mechanisms with transcriptional impact. In contrast, ecDNAs exhibited broad, continuous CN distribution with extreme high-copy outliers, consistent with asymmetric segregation. The CN and structural diversity of ecDNA regions enabled systematic deconvolution of ecDNA subspecies and estimation of their per-cell abundance, revealing the history of ecDNA-mediated oncogenesis at single-nucleotide resolution. We observed ecDNA diversification through internal rearrangements across cases and, notably, convergent evolution in glioblastoma cases marked by multiple, recurrent acquisition of EGFR-targeting ecDNAs. Finally, single-cell genome-based identification of ecDNAs showed substantial discrepancy with bulk genome graph-based predictions and reliably distinguished actively maintained ecDNAs from historical genomic footprints after chromosomal re-integration. These findings reveal marked tissue-type specificity of ecDNAs, suggesting that ecDNA-mediated oncogenesis may depend on a permissive tissue context.

genomics↗

bioRxiv2025

Epigenetic priming promotes acquisition of tyrosine kinase inhibitor resistance and oncogene amplification in human lung cancer

In mammalian cells, gene copy number is tightly controlled to maintain gene expression and genome stability. However, a common molecular feature across cancer types is oncogene amplification, which promotes cancer progression by drastically increasing the copy number and expression of tumor-promoting genes. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification occurs in over 40% of patients tumors. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the mechanisms facilitating oncogene amplification are not fully understood. Here, we find that LUADs exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naive tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. We identified a global chromatin priming effect during the acquisition of TKI resistance, marked by a dynamic increase of H3K27Ac, cohesin loading, and inter-TAD interactions, which occurs before the onset of oncogene amplification. Furthermore, we have found that the METTL7A protein, which was previously reported to localize to the endoplasmic reticulum and inner nuclear membrane, has a novel chromatin regulatory function by binding to amplified loci and regulating cohesin recruitment and inter-TAD interactions. Surprisingly, we discovered that METTL7A remodels the chromatin landscape prior to large-scale copy number gains. Furthermore, while METTL7A depletion has little effect on the chromatin structure and proliferation of drug-naive cells, METTL7A depletion prevents the formation and maintenance of TKI resistant-clones, highlighting the specific role of METTL7A as cells are becoming resistant. In summary, we discovered an unexpected mechanism required for the acquisition of TKI resistance regulated by a largely uncharacterized factor, METTL7A. This discovery sheds light into the maintenance of oncogene copy number and paves the way to the development of new therapeutics for preventing TKI resistance in LUAD.

genetics↗