title: Transcriptionally active regions are the preferred targets for chromosomal HPV integration in cervical carcinogenesis.
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.
authors: Department of Microbiology and Infection Control, Akershus University Hospital, Lørenskog, Norway.
authors: Irene Kraus
authors: IK
authors: Christiansen
authors: Department of Informatics, University of Oslo, Oslo, Norway.
authors: Geir Kjetil
authors: GK
authors: Sandve
authors: Department of Gynaecology, Jena University Hospital, Jena, Germany.
authors: Martina
authors: M
authors: Schmitz
authors: Department of Gynaecology, Jena University Hospital, Jena, Germany.
authors: Matthias
authors: M
authors: Dürst
authors: Department of Informatics, University of Oslo, Oslo, Norway; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.
authors: Eivind
authors: E
authors: Hovig
mesh_terms: D002472:Cell Transformation, Viral; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D009092:Mucous Membrane / Q000378:metabolism; D060787:Neoplasm Grading; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000150:complications* / Q000821:virology*; D014158:Transcription, Genetic; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016662:Virus Integration
chemical_list: D006657:Histones