Why HPV16? Why, now, HPV42? How the discovery of HPV42 in rare cancers provides an opportunity to challenge our understanding about the transition between health and disease for common members of the healthy microbiota.

In 2022, a bioinformatic, agnostic approach identified HPV42 as causative agent of a rare cancer, later confirmed experimentally. This unexpected association offers an opportunity to reconsider our understanding about papillomavirus infections and cancers. We have expanded our knowledge about the diversity of papillomaviruses and the diseases they cause. Yet, we still lack answers to fundamental questions, such as what makes HPV16 different from the closely related HPV31 or HPV33; or why the very divergent HPV13 and HPV32 cause focal epithelial hyperplasia, while HPV6 or HPV42 do not, despite their evolutionary relatedness. Certain members of the healthy skin microbiota are associated to rare clinical conditions. We propose that a focus on cellular phenotypes, most often transient and influenced by intrinsic and extrinsic factors, may help understand the continuum between health and disease. A conceptual switch is required towards an interpretation of biology as a diversity of states connected by transition probabilities, rather than quasi-deterministic programs. Under this perspective, papillomaviruses may only trigger malignant transformation when specific viral genotypes interact with precise cellular states. Drawing on Canguilhem's concepts of normal and pathological, we suggest that understanding the transition between fluid cellular states can illuminate how commensal-like infections transition from benign to malignant.