Multi-omics sequencing study of HPV integration-related cervical cancer

High-risk HPV integration plays a key driving role in the development of cervical cancer, but the molecular mechanism of HPV integration carcinogenesis remains unclear. Here, we combined HPV capture and whole-genome sequencing to identify 649 HPV integration sites in 13 patients and found HPV integration leads to the instability of the host genome. On this basis, we used third-generation transcriptome sequencing technology to generate full-length transcriptome profiles of HSIL and cervical cancer for the first time, then identify abundant unannotated transcripts, gene chimeras, and HPV-human gene fusion transcripts in cervical cancer. We found that only a few HPV DNA integration events can be transcribed to produce HPV-human fusion transcripts, while fusion transcripts have specific structural composition and splicing events. The formation of fusion transcripts is accompanied by overexpression of HPV oncogene E7, disruption of the fused human tumor suppressor genes, and the production of HPV-human fusion gene mRNAs, which leads to cervical cancer. We further verified the carcinogenic function of E1-CMAHP mRNA (E1C, formed by the integration of HPV58 E1 and CMAHP gene) regulating downstream oncogene to participate in multiple biological processes through in vitro experiments. In summary, we found that HPV integration can play a carcinogenic role through the formation of HPV-human gene fusion transcript, and the specific fusion transcript sequences can be a potential marker for the diagnosis and treatment of cervical cancer.