Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis?
An important occurrence in cervical carcinogenesis is deregulated expression of the high-risk human papillomavirus (HR-HPV) oncogenes E6 and E7. Several risk factors for cervical neoplastic progression are likely to contribute to viral oncogene deregulation, particularly integration of HR-HPV into the host genome. Integration represents a by-product of viral infection that is detected in almost 90% of cervical carcinomas. The mechanism of integration is not fully understood, although there is a clear predilection for chromosomal common fragile sites, most likely due to their accessibility for insertion of foreign DNA. Recent work has suggested that an important intermediate stage in cervical carcinogenesis is characterized by transcriptionally silent HR-HPV integrants, which co-exist with viral episomes in infected cells. As episome-derived E2 protein inhibits integrant transcription, clearance of episomes (eg by host innate immunity) is associated with loss of integrant silencing and integrant selection. The process of integration and subsequent clonal selection of integrants can therefore be considered as two independent and biologically distinct events. Indeed, integrated HPV may be viewed as selectable because it represents a form of the virus that is resistant to host mechanisms of viral clearance, enabling infected cells to maintain viral oncogene expression and avoid cell death. Care should be taken in interpreting studies of HPV integration frequency in clinical samples, as the techniques used have assessed either the presence of integrated viral DNA or evidence of transcriptional activity from integrants, but not both.
Pett
M
M
Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge, CB2 0XZ, UK.
Coleman
N
N
D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D005260:Female; D006801:Humans; D027383:Papillomaviridae / Q000302:isolation & purification / Q000502:physiology*; D030361:Papillomavirus Infections / Q000150:complications*; D002583:Uterine Cervical Neoplasms / Q000821:virology*; D016662:Virus Integration; D002578:Uterine Cervical Dysplasia / Q000821:virology