AKT1 loss correlates with episomal HPV16 in vulval intraepithelial neoplasia.
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.
Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Arucha L
AL
Ekeowa-Anderson
Karin J
KJ
Purdie
Karen
K
Gibbon
Carolyn R
CR
Byrne
Jeffrey M
JM
Arbeit
Catherine A
CA
Harwood
Ryan F L
RF
O'Shaughnessy
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000821:virology; D015331:Cohort Studies; D004279:DNA, Viral / Q000235:genetics; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D030361:Papillomavirus Infections / Q000378:metabolism* / Q000821:virology; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000821:virology; D014844:Vulva / Q000378:metabolism / Q000473:pathology / Q000821:virology; D014846:Vulvar Neoplasms / Q000378:metabolism* / Q000821:virology
D004279:DNA, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt