[Human papillomavirus and the development of cervical cancer: concept of carcinogenesis]

Infection with high risk human papillomavirus (hrHPV) plays a central aetiological role in cervical cancer. Still, cervical carcinogenesis is a multistep process which requires other events in addition to hrHPV infection. Recent data have resulted in the following concept of cervical carcinogenesis: hrHPV infects normal squamous epithelium. In most cases this will not lead to a lesion or at worst give rise to a regressing low grade cervical intraepithelial neoplasia (CIN). Both phenomena involve viral clearance. Only persistent hrHPV infections will lead to a high grade CIN lesion, a subset of which may undergo malignant transformation. At the transition of CIN 2 to CIN 3 deregulated expression of the viral oncogenes E6 and E7 takes place, resulting in genetic instability. Subsequently, activation of the telomere-lengthening enzyme, telomerase occurs, at the result of which cells obtain an infinite replication capacity. Ultimately, successive allele losses occur at different chromosomal locations which, followed by a clonal outgrowth result in an invasive carcinoma.