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In Cancer discovery ; h5-index 105.0

The skin is exposed to viral pathogens, but whether they contribute to the oncogenesis of skin cancers has not been systematically explored. Here we investigated 19 skin tumor types by analyzing off-target reads from commonly available next-generation sequencing data for viral pathogens. We identified human papillomavirus 42 (HPV42) in 96% (n = 45/47) of digital papillary adenocarcinoma (DPA), an aggressive cancer occurring on the fingers and toes. We show that HPV42, so-far considered a non-oncogenic, "low-risk" HPV, recapitulates the molecular hallmarks of oncogenic, "high-risk" HPVs. Using machine learning, we find that HPV-driven transformation elicits a germ cell-like transcriptional program conserved throughout all HPV-driven cancers (DPA, cervical carcinoma, and head and neck cancer). We further show that this germ cell-like transcriptional program, even when reduced to the top 2 genes (CDKN2A, SYCP2), serves as a fingerprint of oncogenic HPVs with implications for early detection, diagnosis, and therapy of all HPV-driven cancers.

Leiendecker Lukas, Neumann Tobias, Jung Pauline S, Cronin Shona M, Steinacker Thomas L, Schleiffer Alexander, Schutzbier Michael, Mechtler Karl, Kervarrec Thibault, Laurent Estelle, Bachiri Kamel, Coyaud Etienne, Murali Rajmohan, Busam Klaus J, Itzinger-Monshi Babak, Kirnbauer Reinhard, Cerroni Lorenzo, Calonje Eduardo, Rutten Arno, Stubenrauch Frank, Griewank Klaus G, Wiesner Thomas, Obenauf Anna C