Identification and characterization of eccDNA-driven genes in humans.

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.