Hybrid extrachromosomal DNA in HPV-driven cancers

Extrachromosomal DNA (ecDNA) drives extensive oncogene amplification and intrinsic tumor heterogeneity in human cancers. Recent studies have uncovered an unexpected convergence between viral oncogenesis and ecDNA biology: integration of human papillomavirus (HPV) can trigger the formation of hybrid viral-human ecDNA structures in approximately 30% of HPV-associated oropharyngeal cancers (HPVOPC), with analogous structures reported in cervical cancer models. These chimeric circular elements fuse viral oncogenes with captured human genomic sequences, co-amplifying viral and human genes, and generating de novo enhancer complexes absent from either parental structure. Hybrid ecDNA exhibits canonical ecDNA features, including disproportionately high gene expression, accessible chromatin landscape, and the capacity to act as mobile trans-activating elements that potentiate oncogenic programs. Emerging evidence further suggests that hybrid ecDNA operates through distinct regulatory mechanisms and may create specific therapeutic vulnerabilities that can be leveraged for personalized cancer therapy. Elucidation of the mechanisms governing hybrid ecDNA biogenesis, maintenance, and function may therefore uncover exploitable dependencies in hybrid ecDNA-associated cancers. In this review, we synthesize current insights into hybrid ecDNA formation, regulatory mechanisms, and therapeutic opportunities and discuss how these advances may guide the development of precision cancer therapies.