The Presence of Betapapillomavirus Antibodies around Transplantation Predicts the Development of Keratinocyte Carcinoma in Organ Transplant Recipients: A Cohort Study

Abstract

Organ transplant recipients (OTRs) have an increased risk of developing keratinocyte carcinomas (KCs). The aim of this study was to correlate infection with human papillomaviruses (HPVs) belonging to the beta genus (Beta-papillomavirus (Beta-PV)) at transplantation with later development of KCs. In a cohort study, sera collected between 1 year before and 1 year after transplantation of OTRs transplanted between 1990 and 2006 were tested for antibody responses against the L1 capsid antigen of Beta-PV and other HPV genera (Gamma-, Mu-, Nu-, and Alpha-PV) using multiplex serology. The OTRs were followed for a maximum of 22 years. Cox regression models with KC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) as outcome variables were used. Out of 445 OTRs, 60 had developed KC: 14 developed only SCC, 24 only BCC, and 22 both types of KC. The time-dependent hazard ratio (HR) to develop either or both types of KC, adjusted for age, sex, and transplanted organ, in tested Beta-PV-seropositive OTR around the time of transplantation compared with Beta-PV-seronegative OTR was 2.9 (95% confidence interval (CI) 1.3-6.4). The HR for SCC was 2.9 (95% CI 0.99-8.5) and for BCC it was 3.1 (95% CI 1.2-8.0). There was also an association between Mu-PV seropositivity and KC, but there were no significant associations between other HPV genera tested and KC. A positive seroresponse for Beta-PV around transplantation significantly predicted the development of KC in OTRs up to 22 years later, providing additional evidence that infection with Beta-PV has a role in KC carcinogenesis.

Beta genus papillomaviruses and skin cancer

“…Earlier critical viral activities are not excluded by seronegativity. It is highly interesting that beta HPV seropositivity around transplantation implied a hazard ratio of 2.8 to develop KC in organ transplant recipients, who were followed for up to 22 years (Genders et al, 2014). …”

Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study

“…Case‐control studies in both OTR and immunocompetent populations have shown that the presence of βPV DNA or antibodies was associated with a 1.5‐ to 3‐fold increased risk of cSCC 12, 20, 21, 22, 23, 24, 25, 26, 29, 31, 32. It was not possible, however, to determine whether the βPV infection increases risk of cSCC development or whether cSCC formation promotes active proliferation of βPV.…”

“…It was not possible, however, to determine whether the βPV infection increases risk of cSCC development or whether cSCC formation promotes active proliferation of βPV. To our best knowledge, there is only 1 published cohort study in OTRs that investigated the influence of βPV infection on the development of cSCC 26. In a single‐center study in 445 patients, OTRs who were βPV seropositive around the time of transplantation had an almost 3‐fold increased risk of developing cSCC during the 22‐year follow‐up period 26.…”

“…To our best knowledge, there is only 1 published cohort study in OTRs that investigated the influence of βPV infection on the development of cSCC 26. In a single‐center study in 445 patients, OTRs who were βPV seropositive around the time of transplantation had an almost 3‐fold increased risk of developing cSCC during the 22‐year follow‐up period 26. There are no prospective studies in which the associations between cSCC and both the number and DNA load of βPV types have been examined.…”

Detection of HPV E7 Transcription at Single-Cell Resolution in Epidermis

“…Cutaneous β-HPVs are associated with SCCs in patients with the autosomal recessive disorder epidermodysplasia verruciformis (EV) (Gewirtzman et al, 2008). The burden of β-HPV infection predicts risk of subsequent development of SCC (Farzan et al, 2013), and antibodies to β-HPVs, suggesting active HPV infection, are associated with SCC in immunosuppressed patients (Genders et al, 2015). However, transcription of β-HPV RNA is not observed in healthy skin or in premalignant or malignant skin lesions (Arron et al, 2011), supporting a 'hit-and-run' role for β-HPVs in cutaneous carcinogenesis (Pfister, 2003).…”