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It has been estimated that around 15% of cancer cases worldwide are linked to viral infections, accounting for 1.5 million cases and 1 million deaths per annum. Particularly well studied oncogenic viruses include the human papilloma virus (HPV) linked with cervical cancer, the hepatitis B virus (HBV) linked with liver cancer, and the Epstein-Barr virus (EBV) linked with lymphomas and nasopharyngeal tumours. All these viruses have long latent periods of inactivity, and only a small minority of those infected will go on to develop cancer. The reasons why this infection is either controlled or progresses are largely unknown.

 

New research from the Cancer Epigenetics Group in Spain sheds some light on this question, by looking at patterns of DNA methylation of viral genomes [Fernandez et al. (2009) Genom Res, doi:10.1101/gr.083550.108]. Methylation of DNA is a well studied phenomenon that occurs throughout the genome to alter gene expression in a heritable fashion, so that silencing or activation of a specific gene can be passed on to future generations of cells. It has previously been strongly linked to cancer, through methylation and silencing of tumour suppressor genes (so-called ‘epimutations’).

 

Researchers examined the methylation status of HPV, HBV and EBV genomes in a range of individuals, from asymptomatic healthy carriers, through those with chronically infected tissues and premalignant legions, to those with full-blown invasive tumours. In all cases, they observed that the viral genomes became increasingly methylated as the cancers progressed, leading the authors to suggest that DNA methylation might be a strategy for camouflaging the virus from the human immune system. This has ramifications for the use of DNA demethylating agents in chemotherapy (both approved and in development), which in addition to reactivating tumour suppression genes that have been silenced by methylation, might also reactivate the virus and thereby potentially enhance the therapeutic benefits by increasing the natural immune response.

 

Comment: the finding that viral genomes become increasingly methylated in association with the progression of cancer is perhaps somewhat surprising, given that methylation is usually associated with silencing rather than activation. It therefore suggests a novel mechanism by which the virus exerts its oncogenic effects, and highlights the complex interplay between the host immune system and the viral genome. Regardless of the mechanism, the discovery could have major public health implications in the future for both diagnosis and early treatment of viral cancers.