Viral integration and fusion transcript characteristics of possibly high-risk HPV in cervical cancer

HPV34, HPV66, HPV73, and HPV82 are classified by the International Agency for Research on Cancer as possibly high-risk HPV (pHR-HPV) types. Despite their relatively lower pathogenicity, some cervical cancer (CC) patients have been found to be infected with pHR-HPV, though the underlying pathogenic characteristics remain unclear. Using viral integration detection and RNA sequencing in 8 pHR-HPV⁺ CC samples, we identified that the integration of pHR-HPV into the human genome and the formation of pHR-HPV-human fusion transcripts are critical events in cervical carcinogenesis. These events disrupt normal gene expression and favor the stable expression of oncogenes. Additionally, we discovered that pHR-HPV undergoes alternative splicing from the AGGTA motif. Despite their lower pathogenicity, pHR-HPV integration may represent a significant risk factor for CC development. Our findings underscore the importance of considering pHR-HPV infections in future HPV screening strategies and clinical management of cervical lesions, especially those associated with HPV integration.