List of eccDNAs involved in this study.

Extrachromosomal circular DNA (eccDNA) amplification promotes oncogene expression and cancer development. However, the global transcriptional landscape mediated by eccDNA has not yet been extensively profiled. Here we report a comprehensive analysis spanning cancer, non-cancerous disease and health by developing a new approach to catalog eccDNA-driven genes (EDGs). EDG expression is significantly higher than the average level. Our study identifies 27 common EDGs (CEDGs) existing in most cancer types. Integrated analysis of the CEDGs on gene expression, pathway and network, genetic alteration, epigenetic state, single-cell state, immune infiltration, microbiome and clinically-related features reveals their crucial roles in tumorigenesis and clinical significance. A 17-gene CEDG signature and nomogram was constructed to predict pan-cancer patients’ outcomes. By a novel eccDriver algorithm, 432 candidate eccDNA-driven drivers were identified. We show the candidate drivers regulate five major biological processes including immune system process, developmental process, metabolic process, cell cycle and division, and regulation of transport. 275 of the 432 candidate drivers are clinically actionable with approved drugs. We also demonstrate that eccDNA generation is associated with DNA methylation. Our study reveals general EDG function in humans and provides the most comprehensive discovery of eccDNA-driven driver genes in cancer and non-cancerous diseases to date for future research and application.染色体外环状DNA（extrachromosomal circular DNA, eccDNA）扩增可促进致癌基因表达与癌症发生发展。然而，目前针对eccDNA介导的全局转录组图谱仍未得到充分解析。本研究通过开发全新的编目方法，对eccDNA驱动基因（EDGs）进行归类，并完成了涵盖癌症、非癌性疾病与健康状态的全面分析。EDG的表达水平显著高于基因平均表达水平。本研究鉴定出27种在多数癌症类型中均存在的常见eccDNA驱动基因（CEDGs）。本研究对CEDGs的基因表达、通路与调控网络、遗传变异、表观遗传状态、单细胞特征、免疫浸润、微生物组以及临床相关特征进行整合分析，揭示了其在肿瘤发生中的关键作用与临床价值。本研究构建了包含17个CEDG的基因特征模型与列线图，用于预测泛癌症患者的预后。借助新型eccDriver算法，本研究鉴定出432个候选eccDNA驱动基因。研究表明，这些候选驱动基因调控五大核心生物学过程，涵盖免疫系统过程、发育过程、代谢过程、细胞周期与分裂以及运输调控。在这432个候选驱动基因中，有275个可通过已获批药物实现临床靶向干预。本研究还证实，eccDNA的产生与DNA甲基化水平存在关联。本研究揭示了人类体内EDG的普遍功能，并为当前癌症与非癌性疾病领域提供了迄今为止最为全面的eccDNA驱动基因发现数据集，以供未来研究与应用。