title: Evidence of disrupted high-risk human papillomavirus DNA in morphologically normal cervices of older women.
abstract: High-risk human papillomavirus (HR-HPV) causes nearly 100% of cervical carcinoma. However, it remains unclear whether HPV can establish a latent infection, one which may be responsible for the second peak in incidence of cervical carcinoma seen in older women. Therefore, using Ventana in situ hybridisation (ISH), quantitative PCR assays and biomarkers of productive and transforming viral infection, we set out to provide the first robust estimate of the prevalence and characteristics of HPV genomes in FFPE tissue from the cervices of 99 women undergoing hysterectomy for reasons unrelated to epithelial abnormality. Our ISH assay detected HR-HPV in 42% of our study population. The majority of ISH positive samples also tested HPV16 positive using sensitive PCR based assays and were more likely to have a history of preceding cytological abnormality. Analysis of subsets of this population revealed HR-HPV to be transcriptionally inactive as there was no evidence of a productive or transforming infection. Critically, the E2 gene was always disrupted in those HPV16 positive cases which were assessed. These findings point to a reservoir of transcriptionally silent, disrupted HPV16 DNA in morphologically normal cervices, re-expression of which could explain the increase in incidence of cervical cancer observed in later life.
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Leonard
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Merlin
authors.initials: M
authors.lastname: Pereira
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Roberts
authors.affiliation: Scottish HPV Reference Laboratory, Royal Infirmary of Edinburgh, Edinburgh EH3 6DT, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Cuschieri
authors.affiliation: The Ohio State University, Comprehensive Cancer Center, OH 43210, United States.
authors.forename: Gerard
authors.initials: G
authors.lastname: Nuovo
authors.affiliation: University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, UK.
authors.forename: Ramanand
authors.initials: R
authors.lastname: Athavale
authors.affiliation: Warwick Medical School, University of Warwick, CV4 8UW, UK.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Young
authors.affiliation: Birmingham Women's NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TG, UK.
authors.forename: Raji
authors.initials: R
authors.lastname: Ganesan
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Ciarán B
authors.initials: CB
authors.lastname: Woodman
mesh_terms: D000328:Adult; D000368:Aged; D058070:Asymptomatic Diseases; D002472:Cell Transformation, Viral / Q000235:genetics; D002584:Cervix Uteri / Q000601:surgery / Q000821:virology; D015331:Cohort Studies; D004279:DNA, Viral / Q000235:genetics* / Q000302:isolation & purification; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005404:Fixatives; D005557:Formaldehyde; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D007044:Hysterectomy; D017403:In Situ Hybridization; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000821:virology*; D016133:Polymerase Chain Reaction; D012306:Risk; D013997:Time Factors; D016610:Tissue Embedding; D017735:Virus Latency
chemical_list: D004279:DNA, Viral; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D005404:Fixatives; D009856:Oncogene Proteins, Viral; D005557:Formaldehyde