Long-read sequencing reveals oncogenic mechanism of HPV-human fusion transcripts in cervical cancer
Integration of high-risk human papillomavirus (HPV) into the host genome is a crucial event for the development of cervical cancer, however, the underlying mechanism of HPV integration-driven carcinogenesis remains unknown. Here, we performed long-read RNA sequencing on 12 high-grade squamous intraepithelial lesions (HSIL) and cervical cancer patients, including 3 pairs of cervical cancer and corresponding para-cancerous tissue samples to investigate the full-length landscape of cross-species genome integrations. In addition to massive unannotated isoforms, transcriptional regulatory events, and gene chimerism, more importantly, we found that HPV-human fusion events were prevalent in HPV-associated cervical cancers. Combined with the genome data, we revealed the existence of a universal transcription pattern in these fusion events, whereby structurally similar fusion transcripts were generated by specific splicing in E6 and a canonical splicing donor site in E1 linking to various human splicing acceptors. Highly expressed HPV-human fusion transcripts, eg, HPV16 E6*I-E7-E1