New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections

Abstract

Extensive research over the past 20 years provided strong evidence that persistent infections with high risk type human papillomaviruses (HR-HPVs) cause cervical cancer. However, depending on their age, more than 20% of normal women are infected with these viruses and only very few develop clinically relevant dysplastic lesions or even cancer. During an acute HPV infection, expression of viral genes, in particular the viral E6 and E7 oncogenes is restricted to differentiated epithelial cells, which lost the capability to replicate their genomes and are therefore at no further risk for acquiring functionally relevant mutations upon genotoxic damage. High grade cervical dysplasia, however, is initiated by deregulated expression of viral oncogenes in replicating epithelial stem cells. Here, the E6–E7 gene products submerge control of the cell cycle and mitotic spindle pole formation through complex interactions with various cellular protein complexes and induce severe chromosomal instability. The detailed molecular analysis of these interactions allowed to define new biomarkers for dysplastic cervical cells. E7 for example induces increasing expression of the cyclin dependent kinase inhibitor p16ink4a in dysplastic cells. This can be used to identify dysplastic cells in histological slides, cytological smears or samples taken for biochemical analyses with an yet unmet fidelity. Detection of specific viral mRNAs derived from integrated HPV genomes in advanced precancers can be used to identify lesions with a particularly high risk for progression into invasive carcinomas (APOT assay). These new markers will result in a modified classification of cervical precancers and improved screening assays. Here, we review the basic concept and potential clinical applications of these new developments.