Quantitative TMT-MS of HPV42, HPV16 or empty vector transduced keratinocytes.

The skin serves as a barrier to the environment and is constantly exposed to viral pathogens. Whether viral pathogens contribute to the oncogenesis of rare skin cancers has not been systematically explored. Here, we analyzed 18 skin cancer types by exploiting off-target reads from commonly available next-generation sequencing data. We identified human papillomavirus 42 (HPV42) in all digital papillary adenocarcinoma (DPA) cases but not in any of 11,091 tumors from common cancer types. HPV42 was previously not described as an oncogenic driver, yet we show that HPV42 recapitulates the molecular hallmarks of oncogenic HPVs. Using a machine learning approach, we identified a conserved transcriptomic fingerprint of HPV transformation common to oncogenic HPVs, including HPV42. Collectively, our results establish HPV42 as an oncogenic HPV, which has implications for the diagnosis and treatment for DPA patients.