Liquid Biopsy of HPV Cell-Free DNA Enables Blood-Based Early Detection and Molecular Stratification of HPV-Associated Cancer and Precancer Stages

Liquid biopsies targeting circulating tumor DNA enable noninvasive cancer detection but lack sensitivity in pre- and early-cancer stages, where clinical benefits would be greatest. Human papillomavirus (HPV) causes six cancer types, accounting for 5% of all cancers worldwide. Targeting HPV cell-free (cf)DNA offers a compelling opportunity to overcome current liquid biopsy constraints due to its unique tumor-specific origin, lack of sequence homology to the human genome, and the high viral-to-human copy ratio per cell. Utilizing HPV-associated anal cancer and precancer as a model, here we applied a custom, multi-feature HPV whole-genome liquid biopsy to biobanked and prospective screening coh