Human papillomavirus 42 is an oncogenic driver in Digital Papillary Adenocarcinoma [full_genomes]

The skin serves as a barrier to the environment and is constantly exposed to viral pathogens. However, whether and how viral pathogens contribute to oncogenesis of rare skin cancers has not been explored. We analyzed 18 skin cancers by exploiting sparse off-target reads from commonly available next-generation sequencing data and identify human papillomavirus 42 (HPV42) reads in digital papillary adenocarcinoma (DPA). We show that HPV42 recapitulates the molecular hallmarks of oncogenic HPVs and shares a conserved transcriptomic fingerprint of HPV-transformation. Finally, we show that HPV42 relies on established cellular targets of oncogenic HPVs for its transforming activity. The discovery of HPV42 as a novel oncogenic driver highlights the utility of next-generation sequencing data for the discovery of novel pathogen-disease associations and suggests expansion of current HPV vaccination programs to reduce the cancer burden in humans. Overall design: Cells were transfected with re-circularized HPV genomes and pSV2-neo plasmid.