ASSOCIATION BETWEEN HUMAN PAPILLOMAVIRUS, SOLAR KERATOSES AND SQUAMOUS CELL CARCINOMA OF THE SKIN

Hall, Lisa (2006). ASSOCIATION BETWEEN HUMAN PAPILLOMAVIRUS, SOLAR KERATOSES AND SQUAMOUS CELL CARCINOMA OF THE SKIN PhD Thesis, School of Population Health, University of Queensland.

       
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Author Hall, Lisa
Thesis Title ASSOCIATION BETWEEN HUMAN PAPILLOMAVIRUS, SOLAR KERATOSES AND SQUAMOUS CELL CARCINOMA OF THE SKIN
School, Centre or Institute School of Population Health
Institution University of Queensland
Publication date 2006
Thesis type PhD Thesis
Supervisor Professor Adele Green
Abstract/Summary Background: Squamous cell carcinoma (SCC) of the skin is one of the most common cancers in white-skinned populations world-wide. Solar keratoses (SK) are benign actinic skin tumours that are strongly associated with SCC and are thought to be precursor lesions. The main causal risk factor for both SK and SCC is ultraviolet radiation. Some researchers propose that there may be a role for HPV in skin carcinogenesis. Evidence is emerging from molecular, immunological and epidemiological studies, but to date is not conclusive. The main purpose of this thesis was to investigate the association between epidermodysplasia verruciformis associated human papillomavirus types (EV-HPV) and two types of actinic skin lesions; solar keratoses (SK) and squamous cell carcinoma (SCC). Methods: Two parallel case control studies were designed to examine SK and SCC respectively. Cases for both studies were recruited from a large public hospital and community-based skin cancer clinics in Brisbane, Australia. Hospital-based controls were recruited from general medical and ophthalmology outpatient clinics. Controls were age- and sex-matched to cases. The SK study involved 126 cases with prevalent SK and 58 controls. The SCC study involved 64 cases with incident SCC and 65 controls. Epidemiological data on a variety of risk factors was collected by the investigator at the patient’s study appointment and through the use of a self-completed questionnaire. Serum samples, normal skin biopsies and plucked eyebrow hair samples were collected from participants using standard sterile techniques. Where possible a sample of the SCC from SCC cases was also collected during surgery. Fresh tissue samples and eyebrow hairs were snap frozen using liquid nitrogen before being stored at -70°C. DNA extracted from eyebrow and skin samples was amplified and tested for EV-HPV types 5, 8, 15, 20, 24, 36 and 38 using type-specific Polymerase Chain Reaction (PCR) primers. Serum samples were tested for antibodies against the L1 proteins of EV-HPV types 8, 15, 20, 24 and 38 using virus-like particle enzyme-linked immunosorbent assays (VLP-ELISA). Results: A case-control analysis was performed to examine risk factors for SK and SCC such as pigmentary characteristics and UV exposure, independently of HPV status. Country of birth, propensity to sunburn and tanning ability were strongly associated with both SK and SCC after multivariate modelling. The prevalence and predictors of EV-HPV infection in a subset of healthy controls with no solar keratoses was examined. Antibodies against at least one of the EVHPV types tested were detected in 14% of the tumour-free population; EV-HPV DNA was detected in 16% of normal skin biopsies and 40% of eyebrow hair samples. Across all three biomarkers increasing age was associated with a decreased risk of EV-HPV infection. The associations between EV-HPV and SK; and EV-HPV and SCC were examined using serum antibodies, EV-HPV DNA in normal skin and EV-HPV DNA in plucked eyebrow hairs. Overall EV-HPV seropositivity was positively and significantly associated with both SK and SCC. Seropositivity against multiple EV-HPV types was also positively associated with both SK and SCC, although the association was stronger and significant for SCC. Non-significant positive associations were observed between overall EV-HPV positivity in normal skin and both SK and SCC. SK and SCC cases were slightly more likely than controls to have EV-HPV positive eyebrow hairs. Combination analyses revealed a strong synergistic relationship between EV-HPV and markers of sun-sensitive skin types (fair skin, high propensity to sunburn, inability to tan) to increase the risk of SK and SCC. The joint effect of EV-HPV and UV on the risk of SK/SCC was clearly apparent in serological analyses. This effect was greater for SCC than SK. Discussion: This thesis used a molecular epidemiological approach with multiple biomarkers to investigate the association between EV-HPV infection and SK; and EV-HPV and SCC. Further evidence to support previous literature and the hypotheses is presented. Limitations and advantages of the present project are discussed with reference to existing literature.

 
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