Several viruses are known to be associated with the development of certain cancers, including human papillomavirus (HPV), an established causative agent for a range of anogenital and head and neck cancers. However, much of the available data has analysed causality based on the presence of the virus, or its genetic material, in the sampled tumours. While this approach is a great tool as a starting point to identify possible links, it does not consider the early stages of tumorigenesis, nor the possibility of loss of the viral genetic material during the development of the tumour. Although some cancers were found to be addicted to the continued expression of viral oncogenes, this might not be the case for all virally initiated cancers. Here, we hypothesize that the absence of viral genes from the tumour does not necessarily exclude the viral aetiology. The hit-and-run theory suggests that the viruses have a triggering role in the cancer formation, and the viral genome can be entirely lost after the host cell accumulates numerous mutations. If this mechanism occurs, it will imply that many cancers not associated with viruses might, in fact, have arisen firstly as virus-positive cancers that have lost viral DNA. In this study, we tested this theory in an HPV-driven oropharyngeal cancer (OPC) tumour model. HPV OPCs are oncogenic addicted to the presence of the HPV oncogene, E7, where the genetic removal of this oncogene regresses tumours in vivo. Remarkably, E7 deleted tumours recurred overtime and develop new mutations not previously seen in HPV-positive OPC tumours. Importantly, a number of these new mutations are found to be already present in several HPV-negative OPC tumours. This finding suggests that previously designated HPV-negative OPCs could possibly have begun its carcinogenic journey as an HPV positive tumour and over time lose key viral oncogene(s) to accumulate new mutations for its continual maintenance.