Abstract
Integration of human papillomavirus (HPV) into the host genome is regarded as a determining event in cervical carcinogenesis. However, the exact mechanism for integration, and the role of integration in stimulating cancer progression, is not fully characterized. Although integration sites are reported to appear randomly distributed over all chromosomes, fragile sites, translocation break points and transcriptionally active regions have all been suggested as being preferred sites for integration. In addition, more recent studies have reported integration events occurring within or surrounding essential cancer-related genes, raising the question whether these may reflect key events in the molecular genesis of HPV induced carcinomas. In a search for possible common denominators of the integration sites, we utilized the chromosomal coordinates of 121 viral-cellular fusion transcripts, and examined for statistical overrepresentation of integration sites with various features of ENCODE chromatin information data, using the Genomic HyperBrowser. We find that integration sites coincide with DNA that is transcriptionally active in mucosal epithelium, as judged by the relationship of integration sites to DNase hypersensitivity and H3K4me3 methylation data. Finding an association between integration and transcription is highly informative with regard to the spatio-temporal characteristics of the integration process. These results suggest that integration is an early event in carcinogenesis, more than a late product of chromosomal instability. If the viral integrations were more likely to occur in destabilized regions of the DNA, a completely random distribution of the integration sites would be expected. As a by-product of integration in actively transcribing DNA, a tendency of integration in or close to genes is likely to be observed. This increases the possibility of viral signals to modulate the expression of these genes, potentially contributing to the progression towards cancer.
Highlights
Persistent infection with human papillomavirus (HPV) has been identified as a necessary cause of cervical cancer
A certain overrepresentation of HPV integration sites in transcriptionally active regions, fragile sites and chromosomal instability regions has first of all been attributed to the availability of these regions for the integration event
A general understanding is that the integration event partially is a consequence of a certain level of chromosomal instability caused by the viral E6 and E7 proteins
Summary
Persistent infection with human papillomavirus (HPV) has been identified as a necessary cause of cervical cancer. HPV 16 is the most prevalent type, and together with HPV 18 these are responsible for 70–80% of all cervical cancers, followed by HPV 45, 33 and 31 [2]. Integration of HPV into the host genome is considered as a critical genetic alteration, and is regarded as a determining event in cervical carcinogenesis [5]. Integration may result in the up-regulation of E6/E7 expression, and in that way contributes to carcinogenesis [4]. High levels of E6/E7 expression are not always seen [6]. Additional possible consequences of viral integration are under investigation, and the role of HPV integration in the process of tumor progression is an area of high importance in understanding the etiology of the disease
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