DNA viruses in human cancer: established oncogenic mechanisms, emerging virus–tumour associations and clinical implications

DNA virus-associated tumours represent an important component of the global burden of infection-associated cancer. Studies of classical DNA tumour viruses have defined major oncogenic routes, including persistent viral oncoprotein expression, chronic inflammation and tissue regeneration, viral integration and immune evasion. This work has also facilitated clinical applications of vaccines, antiviral therapies and viral biomarker testing. Recent advances in cancer genomics and molecular pathology have identified several biologically distinctive virus–tumour associations. These include TTMV::RARA fusion-driven APL-like acute myeloid leukaemia, HPV42-associated digital papillary adenocarcinoma, AAV2 insertions in a subset of hepatocellular carcinomas and transplant-associated BKPyV-positive urothelial carcinoma. The significance of these associations lies not in expanding the catalogue of tumour viruses, but in revealing distinct molecular events. These encompass virus–host fusion, tissue-specific viral oncogene expression, insertion-mediated cis activation and persistent T-antigen expression under immunosuppression. Here, we outline the principal mechanisms of classical DNA tumour viruses and compare the molecular basis, modes of tumour maintenance and potential clinical value of these recently recognised associations. We also discuss detection strategies, evidentiary boundaries and priorities for future research. Current evidence indicates that event-matched assays may support specialist ancillary diagnosis or molecular classification in selected settings, particularly for APL-like leukaemia and DPA. However, none of the four emerging associations currently supports population screening or a virus-directed standard therapy, and research-stage applications require prospective validation.