Integration of HPV DNA into a host genome has been shown to positively correlate with the severity of the lesions, supporting the hypothesis that integration is an important event during carcinogenesis. The main effect of viral integration is the loss of E2 gene sequences through disruption of the episomal genome. HR-HPV genomes replicate as episomal molecules in the normal viral life cycle. Despite being controlled by E2 (12), E6 and E7 induce severe chromosomal instability associated with centrosome aberrations, anaphase bridges, chromosome lagging, and breaking. Integration seems to be a direct consequence of chromosomal instability and an important molecular event in the progression of preneoplastic lesions. Disruption or deregulation of defined critical cellular gene functions by insertional mutagenesis (13) and by integrated HPV genome 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. Ferber et al. (14,15) described HPV integration to occur within or close to the MYC gene locus and in the area of the telomerase gene. Thus, it is conceivable that interference of viral sequences with critical cellular sequences contribute essentially to the enhanced progression risk of HPV-induced preneoplasia into neoplastic lesions.
Another possible explanation for progression toward malignant lesions after HR-HPV integration might be structural changes of the viral genome that allow enhanced and deregulated expression of the viral oncogenes and thereby confer the additional neoplas-tic advantage. It was shown that HPV E6- and E7-encoding complementary DNAs derived from integrated viral oncogene transcripts, confer a much stronger transforming capacity in primary cells as compared with complementary DNAs derived from episome-derived transcripts. This was attributed to the longer half-life of transcripts derived from integrated HPV DNA, mediated by 3-cellular sequences of the fusion transcripts (16). In specific cervical cancer cell lines only one or few integrated genomes are transcribed, whereas (17) clinical samples harbor only few integration sites, with the majority thereof being actively transcribed (18). Taken together, these observations suggest that integration of the viral genome renders viral gene expression independent of viral control mechanisms and allows selection of cell clones with deregulated viral oncogene expression favoring the outgrowth of neoplastic cell clones.
Two different assays have been applied to analyze genomic HPV integration sites: the first is the "detection of integrated papillomavirus sequences polymerase chain reaction," which detects the integration site of the virus at the human genome on DNA probe. The other test is the amplification of papillomavirus oncogene transcripts assay, which detects transcripts of integrated viral DNA. Both tests open the future to the possibility of using viral integration as the surrogate marker for progression of precursors to invasive cancer.
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