Abstract

Anogenital malignancy has a significant association with high-risk mucosal alpha-human papillomaviruses (alpha-PV), particularly HPV 16 and 18 whereas extragenital SCC has been linked to the presence of cutaneous beta and gamma–HPV types. Vulval skin may be colonised by both mucosal and cutaneous (beta-, mu-, nu- and gamma-) PV types, but there are few systematic studies investigating their presence and their relative contributions to vulval malignancy. Dysregulation of AKT, a serine/threonine kinase, plays a significant role in several cancers. Mucosal HPV types can increase AKT phosphorylation and activity whereas cutaneous HPV types down-regulate AKT1 expression, probably to weaken the cornified envelope to promote viral release. We assessed the presence of mucosal and cutaneous HPV in vulval malignancy and its relationship to AKT1 expression in order to establish the corresponding HPV and AKT1 profile of normal vulval skin, vulval intraepithelial neoplasia (VIN) and vulval squamous cell carcinoma (vSCC). We show that HPV16 is the principle HPV type present in VIN, there were few detectable beta types present and AKT1 loss was not associated with the presence of these cutaneous HPV. We show that HPV16 early gene expression reduced AKT1 expression in transgenic mouse epidermis. AKT1 loss in our VIN cohort correlated with presence of high copy number, episomal HPV16. Maintained AKT1 expression correlated with low copy number, an increased frequency of integration and increased HPV16E7 expression, a finding we replicated in another untyped cohort of vSCC. Since expression of E7 reflects tumour progression, these findings suggest that AKT1 loss associated with episomal HPV16 may have positive prognostic implications in vulval malignancy.

Highlights

  • Human papillomaviruses (HPV) are a family of over 120 small double-stranded DNA viruses with mucosal or cutaneous epitheliotropism [1]

  • These findings suggest that the squamous keratinising epithelial component of vulval skin is similar to extragenital epidermis and may be susceptible to infection by cutaneous HPV types as well as alpha high risk HPV types

  • As AKT1 loss was only detected in a subset of HPV16 positive vulval intraepithelial neoplasis (VIN), we investigated whether this correlated with the physical status of the viral genome; we hypothesise that only episomal HPV16 is capable of lifecycle completion which concomitantly requires AKT1 down-regulation [11]

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Summary

Introduction

Human papillomaviruses (HPV) are a family of over 120 small double-stranded DNA viruses with mucosal or cutaneous epitheliotropism [1]. The mucosal alpha-papillomavirus (alphaPV) genus contains high-risk HPV types, such as HPV 16 and 18, which are causal in cervical intraepithelial neoplasia (CIN) and cervical cancer [2]. Cutaneous beta-PVs are ubiquitous in skin and hair follicles. They are associated with cutaneous squamous cell carcinoma (SCC) development in the genodermatosis epidermodysplasia verruciformis and may act as co-factors with ultraviolet radiation (UVR) in the pathogenesis of cutaneous SCC arising outside the context of EV, in immunosuppressed individuals [3]. Less common than cervical cancer, vulval squamous cell carcinoma (vSCC) and its precursor, vulval intraepithelial neoplasis (VIN), are increasing in incidence [5].

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