Vaccination against a hit-and-run viral cancer

Department of Pathology, University of Cambridge, UK.
Journal of General Virology (Impact Factor: 3.18). 09/2010; 91(Pt 9):2176-85. DOI: 10.1099/vir.0.023507-0
Source: PubMed


Cancers with viral aetiologies can potentially be prevented by antiviral vaccines. Therefore, it is important to understand how viral infections and cancers might be linked. Some cancers frequently carry gammaherpesvirus genomes. However, they generally express the same viral genes as non-transformed cells, and differ mainly in also carrying oncogenic host mutations. Infection, therefore, seems to play a triggering or accessory role in disease. The hit-and-run hypothesis proposes that cumulative host mutations can allow viral genomes to be lost entirely, such that cancers remaining virus-positive represent only a fraction of those to which infection contributes. This would have considerable implications for disease control. However, the hit-and-run hypothesis has so far lacked experimental support. Here, we tested it by using Cre-lox recombination to trigger transforming mutations in virus-infected cells. Thus, 'floxed' oncogene mice were infected with Cre recombinase-positive murid herpesvirus-4 (MuHV-4). The emerging cancers showed the expected genetic changes but, by the time of presentation, almost all lacked viral genomes. Vaccination with a non-persistent MuHV-4 mutant nonetheless conferred complete protection. Equivalent human gammaherpesvirus vaccines could therefore potentially prevent not only viral genome-positive cancers, but possibly also some cancers less suspected of a viral origin because of viral genome loss.

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    • "Hit-and-run oncogenesis is most frequently considered in the context of virally induced cancers.28 The idea that cancer progression can persist in the absence of initiating viral oncoprotein expression is supported by laboratory models in which a transformed cellular phenotype persists despite loss of viral oncoprotein expression for adenoviruses,29,30 herpesviruses,31,32 and the polyomavirus Simian virus 40 (SV40) large T antigen (TAg).33–37 Hit-and-run–mediated pathophysiology has been suggested as a pathway for polyomavirus in human brain tumors and mesotheliomas,38–40 JC virus in colorectal cancer,41 papillomaviruses in Schneiderian inverted papillomas,42 and Hepatitis B in hepatomas.43 "
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    ABSTRACT: Background: Oral cavity and in particular oral tongue cancers occur with a rising incidence in younger patients often lacking the typical risk factors of tobacco use, alcohol use, and human papilloma virus (HPV) infection. Their prognosis when treated with chemoradiation has not been well studied and responsible risk factors remain elusive. A viral etiology (other than HPV) has been hypothesized. Methods: First we analyzed outcomes from 748 head and neck cancer patients with locoregionally advanced stage tumors treated with curative-intent chemoradiation by anatomic site. Second, we analyzed seven oral tongue (OT) tumors from young, non-smokers/non-drinkers for the presence of viral mRNA using short-read massively-parallel sequencing (RNA-Seq) in combination with a newly-developed digital subtraction method followed by viral screening and discovery algorithms. For positive controls we used an HPV16-positive HNC cell line, a cervical cancer, and an EBV-LMP2A transgene lymphoma. Results: Younger patients with oral cavity tumors had worse outcomes compared to non-oral cavity patients. Surprisingly none of the seven oral tongue cancers showed significant presence of viral transcripts. In positive controls the expected viral material was identified. Conclusion: Oral cavity tumors in younger patients have a poor prognosis and do not appear to be caused by a transcriptionally active oncovirus.
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Stacey Efstathiou