Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract

Cancers of the anogenital tract as well as some head and neck cancer are caused by persistent infections with high-risk type human papilloma- viruses (HPVs). Two viral oncogenes, E6 and E7, induce severe chromo somal instability associated with centrosome aberrations, anaphase bridges, chromosome lagging, and breaking. This occurs early in preneo-plastic lesions, when the viral genome still persists in an episomal state. In most invasive cancers and also in a few high-grade dysplastic lesion however, integration of high-risk HPV genomes into the host genome observed. Integration seems to be a direct consequence of chromosomal instability and an important molecular event in the progression of pre-neoplastic lesions. Disruption or deregulation of defined critical cellula gene functions by insertional mutagenesis. by integrated HPV genom fragments has been hypothesized as one major promoting factor in the pathogenesis of HPV-associated cancers. This hypothesis was based on the detection of HPV integration events in the area of tumor-relevant genes in few cases. Here, we reviewed >190 reported integration loci with respect to changes in the viral structure e and the targeted genomic locus. This analysis confirms that HPV integration sites are randomly distribute over the whole genome with a clear predilection for genomic fragile site No evidence for targeted disruption or functional alteration of critical cellular genes by the integrated viral sequences could be found.