Fig. 2. Oncogenesis of HPV⁺ oropharyngeal cancers.

a | Major events in the development of human papillomavirus (HPV)-driven malignancy based on the established stepwise model of cervical carcinogenesis. HPV infection is established in the basal layer of the epithelium, with access facilitated either through micro-abrasions or, in the case of the oropharynx, potentially owing to the reticulated nature of the epithelium of the tonsillar crypts. Productive infections are usually cleared by the immune system but if not, deregulation of E6 and E7 expression can occur, causing exit from the productive viral life cycle and the development of neoplasia (in the cervix this is evident as lesions detectable by screening but no such lesions have been identified in the oropharynx). E6 and E7 suppress important mechanisms of tumour suppression and cause epigenetic changes, which can combine with somatic alterations in the host cell genome to cause transformation and progression to malignancy. In the cervix, these events typically occur over the course of 10–20 years after the causative HPV infection^60,61. b | Schematic showing how HPV-driven oncogenic processes act to enable seven of the eight hallmarks of cancer originally defined by Hanahan and Weinberg⁶⁸ and how experimental therapies are able to disable one or more of these hallmarks^66,67,240.