Non-melanoma skin cancer (NMSC), comprised of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is the most common cancer in Caucasians. Ultraviolet radiation (UVR) exposure is the most important environmental risk factor for both BCC and SCC development. However, the precise relationship between UVR and the risk of NMSC is complex, and the relationship may differ by skin cancer type. It has been hypothesized that intermittent patterns and childhood sunlight exposure are important for BCC while continuous (chronic) and lifelong (i.e. childhood and adulthood) sunlight exposure is important for SCC. Epidemiologic studies have demonstrated that cutaneous human papillomavirus (HPV) infection may also be a risk factor for developing NMSC. However, the pathway by which cutaneous HPV is associated with NMSC remains unclear. It is hypothesized that UVR exposure may interact synergistically with cutaneous HPV in NMSC development. The goal of the research study was to evaluate the relationship between levels of sunlight exposure and BCC and SCC and to investigate differences in sunlight-associated BCC and SCC risk by genus-specific cutaneous HPV serostatus. To address these goals, we conducted a clinic based case-control study of histologically confirmed BCC and SCC cases recruited from a university dermatology clinic and controls with no history of cancer and screened negative for current skin cancer. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the associations between measures of sunlight exposure and BCC and SCC. Multiplicative interactions were tested by placing an interaction term for the product of genus-specific HPV seroreactivity and sunlight related factors in the logistic regression models. Measures of both intermittent and continuous patterns of sunlight exposure were associated with both types of skin cancer (i.e. BCC and SCC). Specifically, history of blistering sunburn (a marker of intermittent sunlight exposure) and occupational sunlight exposure (i.e. having a job in the sun for at least 3 months for >10 years) were both associated with BCC and SCC. The major differences in patterns of sunlight exposure between BCC and SCC were observed for sunlight exposure in one's thirties. Additionally, sunlight exposure in one's twenties was associated with SCC, regardless of pattern of exposure; similar associations were not observed for BCC. Measures of timing of sunlight exposure consistently demonstrated that childhood/adolescent sunlight exposure was more important for SCC than BCC. These included number of moles on the forearms and entire body (measure of increased childhood sunlight exposure), and younger age at first and tanning bed use. Younger age at first blistering sunburn was statistically significantly associated with both BCC and SCC. NMSC cases were more likely to be seropositive for cutaneous HPV antibodies compared to controls. Compared to tanning, having a propensity to sun burn (p=0.006), or poor tanning ability (p=0.003) were significantly associated with a higher seroprevalence to genus beta HPV types within SCC cases. Statistically significant interactions were observed between poor tanning ability and genus-specific seropositivity with NMSC. Specifically, the associations between poor tanning ability and BCC (p interaction=0.02) and SCC (p interaction=0.01) were significantly stronger among individuals that were seropositive for antibodies to genus alpha HPV types. Similarly, the association between poor tanning ability and SCC was stronger among those seropositive for genus beta HPV types (p interaction=0.001). No additional significant interactions were observed for BCC or SCC between cutaneous sensitivity, history of blistering sunburn, or cumulative sunlight exposure and genus-specific seroreactivity. In conclusion, associations with patterns of sunlight exposure appeared to be similar between BCC and SCC cases. With the exception of age at first blistering sunburn, factors measuring timing of sunlight exposure demonstrated stronger and statistically significant relationships with SCC. Additionally, of the sunlight related factors measured, only the associations between poor tanning ability and BCC and SCC were significantly modified by HPV seropositivity to types in genera alpha or beta.

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