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.
Highlights
High-risk human papillomavirus (HR-HPV) causes nearly 100% of cervical carcinoma
The United Kingdom NHS Cervical Screening Programme (NHS CSP) has for many years achieved excellent coverage in women aged between 50 and (~80%), one in five cancers still occur in women aged or older; and 49% of all deaths from cervical cancer are in this age-group[1,2]
How do we explain the development of cervical cancer in women who exit the screening programme at 65 with a history of normal smear tests over the preceding fifteen years? It has been argued that incident cervical HPV infections are uncommon in women over the age of 65 and that in any event, the extended natural history of cervical neoplasia makes it improbable that these infections would have sufficient time to progress to invasive cancer
Summary
High-risk human papillomavirus (HR-HPV) causes nearly 100% of cervical carcinoma. 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. A recent NHS CSP audit which included 1341 cervical cancers diagnosed in women aged 65–83 suggested that this is no longer the case. Many of these women exited the screening programme with negative smear tests; 44% had at least three negative smears after the age of 501. The most compelling evidence for HPV latency comes from in vivo studies using the rabbit oral papillomavirus model These experiments point to a model of virus latency in which papillomaviruses retained under immunological control in the basal epithelial stem cell pool can be induced to reactivate periodically[6]. Given that we have a highly HPV exposed and ageing population there is a need for a clearer understanding of the potential for virus reactivation in later life and the implications this might have for our current cancer prevention and managment strategies
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