title: Pathogenesis of human papillomavirus-associated mucosal disease.
abstract: Human papillomaviruses (HPVs) are a necessary cause of carcinoma of the cervix and other mucosal epithelia. Key events in high-risk HPV (HRHPV)-associated neoplastic progression include persistent infection, deregulated expression of virus early genes in basal epithelial cells and genomic instability causing secondary host genomic imbalances. There are multiple mechanisms by which deregulated virus early gene expression may be achieved. Integration of virus DNA into host chromosomes is observed in the majority of cervical squamous cell carcinomas (SCCs), although in ∼15% of cases the virus remains extrachromosomal (episomal). Interestingly, not all integration events provide a growth advantage to basal cervical epithelial cells or lead to increased levels of the virus oncogenes E6 and E7, when compared with episome-containing basal cells. The factors that provide a competitive advantage to some integrants, but not others, are complex and include virus and host contributions. Gene expression from integrated and episomal HRHPV is regulated through host epigenetic mechanisms affecting the virus long control region (LCR), which appear to be of functional importance. New approaches to treating HRHPV-associated mucosal neoplasia include knockout of integrated HRHPV DNA, depletion of virus transcripts and inhibition of virus early gene transcription through targeting or use of epigenetic modifiers. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: University of Cambridge, Department of Pathology, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Groves
authors.forename: Nicholas
authors.initials: N
authors.lastname: Coleman
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy / Q000821:virology*; D002472:Cell Transformation, Viral; D002584:Cervix Uteri / Q000473:pathology / Q000821:virology*; D004279:DNA, Viral / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy; D054884:Host-Pathogen Interactions; D006801:Humans; D009092:Mucous Membrane / Q000473:pathology / Q000821:virology; D009857:Oncogenes; D027383:Papillomaviridae / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification / Q000472:pathogenicity*; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy / Q000821:virology*; D012367:RNA, Viral / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy / Q000821:virology*
chemical_list: D004279:DNA, Viral; D012367:RNA, Viral
keywords: E6/E7; epigenetics; human papillomavirus; integration; mucosa; oncogene; squamous cell carcinoma