The Urinary eccDNA Landscape in Prostate Cancer Reveals Associations with Genome Instability and Vital Roles in Cancer Progression

We pioneered the profiling of urinary cell-free eccDNAs landscape in PCa and uncovered a high association between eccDNA generation and active chromatin status as well as gene transcription. Double strand breaks and R-loops, which preferentially occur in active genomic sites and cause genome instability, can promote eccDNA generation. Genome instability frequently results in genomic mutations, and our study further established a link between eccDNA generation and oncogenic mutations. Additionally, genes specifically exhibiting high eccDNA generation frequency (HFGs) in PCa contributed to PCa progression and were associated with poorer survival outcomes in PCa patients. Finally, we demonstrated that eccDNAs derived from PCa-specific HFGs, in contrast to intergenic eccDNAs, could suppress PCa cell proliferation and migration, which was independent of their host gene expression.

本研究率先开展了前列腺癌（Prostate Cancer, PCa）患者尿游离环状染色体外DNA（extrachromosomal circular DNAs, eccDNAs）的全景图谱分析，揭示了eccDNA生成与染色质活化状态及基因转录之间的显著关联。双链断裂与R环优先富集于活化基因组区域并诱发基因组不稳定，可促进eccDNA生成。基因组不稳定常引发基因组突变，本研究进一步明确了eccDNA生成与致癌突变之间的关联。此外，在前列腺癌中特异性呈现高eccDNA生成频率的基因（High Frequency Genes, HFGs）可促进前列腺癌进展，且与前列腺癌患者不良预后密切相关。最后，本研究证实，相较于基因间区eccDNAs，源自前列腺癌特异性高eccDNA生成频率基因的eccDNAs可抑制前列腺癌细胞的增殖与迁移，且该效应不依赖于其宿主基因的表达水平。