Molecular characterization of HPV integrations in high-risk HPV-positive women and development of a prognostic signature based on integration-associated genes for cervical cancer

BACKGROUND: HPV integration into the human genome is a key molecular event in the progression of cervical cancer carcinogenesis. METHODS: This study utilized samples from high-risk HPV-positive women to investigate HPV integration. Integration-associated genes were screened based on HPV-DNA integration sequencing data from our local clinical cohort, and their expression levels and prognostic value were independently validated and used for model construction in the TCGA-CESC RNA-seq dataset. Using this integration-associated prognostic risk model, cervical cancer (CC) patients from TCGA were stratified into high-risk and low-risk groups. Differences in enrichment of PI3K-AKT pathway genes and immunotherapy response were analyzed between the two groups, and functional analysis was performed on differentially expressed immune-related genes between the subgroups. RESULTS: The HPV integration rate gradually increases with the progression of cervical disease. The most frequent integration-related genes were KLF5, LINC00392, BCL11B and TP63. A risk model based on eight HPV integration-associated genes was developed, which could classify CC samples into high-risk groups with significantly shorter overall survival times compared to low-risk groups (P < 0.001). ROC curve evaluation showed that the AUCs for the 3, 5, and 7-year survival rates were 0.77, 0.74, and 0.76, respectively. The significant differences in PI3K-AKT pathway gene enrichment and prediction of immune therapy response were found between two risk groups. CONCLUSION: A integration-associated prognostic risk model based on genes derived from HPV integration hotspots shows significant association with patient survival and is correlated with distinct tumor microenvironment features, including PI3K-AKT pathway activity and predicted immunotherapy response.