HPV DNA Integration at Actionable Cancer-Related Genes Loci in HPV-Associated Carcinomas

Area of Science:

• Oncology
• Virology
• Genetics

Background:

• Human papillomavirus (HPV) infection is a major cause of various carcinomas.
• Viral integration into the host genome can alter cancer-related genes, presenting potential therapeutic targets.
• Quantitative assessments of these integration events, particularly for less frequent targets, are lacking.

Purpose of the Study:

• To quantitatively assess host DNA sequences targeted by HPV integration in HPV-associated cancers.
• To identify and characterize cancer-related genes and potential therapeutic targets affected by viral insertion.
• To investigate the relationship between HPV genotypes, tumor localization, and targeted gene recurrence.

Main Methods:

• Construction and analysis of a database comprising 1455 HPV-associated carcinoma cases.
• Classification of host DNA integration sites into non-recurrent, weakly recurrent, and highly recurrent categories.
• Comparison of cancer-related gene targeting rates between different recurrence categories and HPV genotypes.
• Analysis of druggable targets among HPV-integrated genes using literature and DepMap database.

Main Results:

• A significant increase in cancer-related gene targeting was observed with increasing recurrence of HPV integration sites (6.5% non-recurrent to 40.1% highly recurrent).
• High-risk HPV genotypes (16/18/45) were associated with a higher rate of cancer-related gene targeting.
• Approximately 30.2% of all targeted genes were druggable, rising to 50% in highly recurrent targets.
• Genes targeted by viral insertion emerged as potential candidates in HPV-driven oncogenesis.

Conclusions:

• HPV integration events disproportionately target cancer-related genes, with a strong correlation between recurrence frequency and the likelihood of targeting such genes.
• A substantial proportion of HPV-targeted genes are druggable, highlighting their therapeutic potential.
• Systematic characterization of HPV/host fusion sequences is crucial for understanding HPV-driven carcinogenesis and developing personalized treatments.