Kristina M. Michael

Seroprevalence of 34 Human Papillomavirus Types in the German General Population

The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age- and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life.

Genus β human papillomaviruses and incidence of basal cell and squamous cell carcinomas of skin: population based case-control study

Objective To investigate the association between genus β human papillomaviruses and the incidence of non-melanocytic skin cancer in the general population. Design Population based case-control study. Setting New Hampshire, USA. Participants 2366 skin cancer cases and controls from the general population aged 25 to 74 years (663 squamous cell carcinoma, 898 basal cell carcinoma, 805 controls), with plasma samples tested for L1 antibodies to 16 genus β human papillomaviruses by multiplex serology. Main outcome measures Odds ratios for squamous cell carcinoma and basal cell carcinoma associated with seropositivity to β human papillomaviruses. Results Squamous cell carcinoma, but not basal cell carcinoma, cases had a higher prevalence of each of the individual β human papillomaviruses assayed compared with controls. The odds ratios for squamous cell carcinoma increased with the number of β types positive (odds ratio for one type positive 0.99 (95% confidence interval 0.74 to 1.33); two to three types positive 1.44 (1.03 to 2.01); four to eight types positive 1.51 (1.03 to 2.20); more than eight types positive 1.71 (1.12 to 2.62); P for trend (categorical)<0.001; P for trend (continuous)=0.003). With limited statistical power, the association was stronger among long term users of systemic glucocorticoids (odds ratio 3.21, 1.22 to 8.44) than among non-users (1.23, 0.97 to 1.55). Conclusions These findings support a relation between genus β human papillomavirus infection and the incidence of squamous cell carcinoma of the skin in the general population, as well as potential enhancement of risk by immunosuppression.

Serological association of beta and gamma human papillomaviruses with squamous cell carcinoma of the skin.

Background  Cutaneous human papillomaviruses (HPVs) may play a role in the development of squamous cell carcinomas (SCC) of the skin.

A prospective pilot study of antibodies against human papillomaviruses and cutaneous squamous cell carcinoma nested in the Oxford component of the European Prospective Investigation into Cancer and Nutrition.

In a prospective pilot study nested in the EPIC‐Oxford cohort, we examined the seroprevalence of antibodies against the L1 antigen of 38 human papilloma virus (HPV) types among 39 cases of cutaneous squamous cell carcinoma (SCC) for whom plasma was collected prior to diagnosis (incident) and 80 controls. Fifteen cases having already developed SCC at blood collection (prevalent) were also tested. There were no statistically significant differences in the seroprevalence of antibodies against any of the HPV types examined between incident cases and controls, nor was there a difference in the seroprevalence of multiple infections. However, consistent with results from published case–control studies, the seroprevalence of many β‐HPV types was higher among prevalent cases than among either incident cases or controls. For example the seroprevalence of antibodies against HPV‐8 was 20% (16/80) in controls, 23% (9/39) among incident cases and 40% (6/15) among prevalent cases. Among the incident cases only, the seroprevalence was 16% (5/32) among those for whom blood was collected 18+ months prior to diagnosis, but 57% (4/7) among those for whom diagnosis was within 18 months of blood collection, a pattern seen for many of the HPV types. This might suggest that if HPV is involved in the aetiology of SCC, the process occurs close to the time of diagnosis, or that the antibody response observed in people with SCC is a consequence of tumor formation. Further and larger prospective studies are needed to clarify the role of HPV in the aetiology of cutaneous SCC.

High β-HPV DNA Loads and Strong Seroreactivity Are Present in Epidermodysplasia Verruciformis

Epidermodysplasia verruciformis (EV) is a rare disease, characterized by cutaneous warts and associated with a strong predisposition to beta-genus human papillomavirus (HPV). Earlier studies reported high copy numbers of HPV-DNA in nearly all skin tumors from EV patients, but neither HPV replication status in non-lesional skin nor anti-HPV seroreactivity in these patients have been reported yet. We therefore performed a comprehensive viral load analysis for the more common beta-HPV types on skin samples and plucked eyebrow hairs from four EV patients treated at our dermatology department. The results clearly demonstrate that they carry a multiplicity (up to eighteen types) of beta-HPV genotypes in both skin sites. Worthy of note, a high intrapatient concordance for specific types between hair bulbs and skin biopsies was observed and the same beta-PV profile was maintained over time. Viral load analysis revealed a load range between less than one HPV-DNA copy per 100 cells to more than 400 HPV-DNA copies per cell in both eyebrow hairs and skin proliferative lesions. Evaluation of seroreactivity to beta-HPV types in the four EV patients revealed that antibodies against the 16 beta-HPV were significantly more prevalent and showed higher titers than in the controls.

Case–Control Study of Cutaneous Human Papillomaviruses in Squamous Cell Carcinoma of the Skin

Background: Cutaneous human papillomavirus (HPV) infection may be a risk factor for squamous cell carcinoma (SCC) of the skin. Methods: To investigate the association between cutaneous HPV and SCC, a case–control study was conducted, including 173 SCC cases from a university dermatology clinic and 300 controls that screened negative for skin cancer. Serum antibodies against cutaneous HPV types in genera alpha, beta, gamma, mu, and nu were measured. Tumor tissue from 159 SCC cases was tested for the presence of DNA for genus-beta HPV types. Using logistic regression ORs and 95% confidence intervals (CI) were estimated for the associations between SCC and cutaneous HPV infection, adjusting for age and sex. The Bonferroni method was used to account for multiple comparisons. Results: SCC was positively associated with seropositivity to any genus-beta HPV type (OR, 1.93; 95% CI, 1.23–3.02), particularly with types in species-1 (OR, 1.86; 95% CI, 1.22–2.85). Type-specific associations with SCC were observed for HPV 8 (OR, 1.80; 95% CI, 1.14–2.84), 17 (OR, 1.59; 95% CI, 1.02–2.49) and HPV 10 from genus-alpha (OR, 2.24; 95% CI, 1.04–4.85). None of the type-specific associations remained statistically significant after correction for multiple comparisons. When DNA-positive SCC cases were compared with controls, strong serologic associations were observed for HPVs 5 (OR, 3.48; 95% CI, 1.27–9.59), 17 (OR, 3.36; 95% CI, 1.29–8.72), and 24 (OR, 3.79; 95% CI, 1.24–11.5). Conclusion: Genus-beta HPV infections were associated with SCC in our study population. Impact: Identifying the role of cutaneous HPV infection in SCC may lead to improved characterization of high-risk individuals and the development of novel prevention strategies. Cancer Epidemiol Biomarkers Prev; 21(8); 1303–13. ©2012 AACR.

Dynamics of human papillomavirus serology in women followed up for 36 months after pregnancy

We determined L1 antibodies for human papillomavirus (HPV) types 6, 11, 16, 18 and 45 by multiplex serology in our prospective HPV family study. We report seroprevalence, seroconversion and antibody decay in 290 women (mean age, 25.5 years) sampled before delivery and at 12, 24 and 36 months of follow-up. Multiplex HPV genotyping of the baseline oral and genital scrapings was performed. At baseline, seroprevalence of HPV 6, 11, 16, 18 and 45 was 53.3, 21.5, 34.9, 21.5 and 9.0%, respectively. Seropositivity for low-risk HPV (LR-HPV) was associated significantly with age at onset of sexual activity (P=0.001), number of sexual partners until age 20 (P=0.018), lifetime number of sexual partners (P=0.0001), history of genital warts (P=0.0001) and being seropositive for high-risk (HR) HPV (P=0.0001). The same covariates also predicted seropositivity for HR-HPV. During follow-up, 26.7, 13.9, 17.0, 16.8 and 6.6% of the women seroconverted to L1 antigen of HPV 6, 11, 16, 18 and 45, respectively, between 18.2 and 23.8 months. Independent predictors of seroconversion to LR-HPV were unemployment (P=0.019) and absence of anal sex practice (P=0.031), and to HR-HPV, absence of smoking history and lifetime number of sexual partners. Decay of HPV 6, 11, 16, 18 and 45 antibodies was observed in 2.3, 4.0, 5.3, 4.5 and 1.5 % of the women, respectively, with decay time varying from 27.2 to 35.8 months. These data imply that (i) a substantial proportion of young women are seropositive for both LR- and HR-HPV types, (ii) they frequently undergo seroconversion within 18-24 months, predicted by common covariates, and (iii) antibody decay over 3 years is rare.

Antibody responses to 26 skin human papillomavirus types in the Netherlands, Italy and Australia

Solar UV radiation is the main risk factor for cutaneous squamous cell carcinoma (SCC), but infections with skin human papillomavirus (HPV) types have also been linked to the development of SCC. Little is known about the natural history of these infections and whether the seroprevalence of skin HPV types is affected by ambient or individual levels of sun exposure. This study investigated this by analysing sera for antibodies to 26 skin HPV types from five phylogenetic genera obtained from 807 healthy individuals from the Netherlands, Italy and Australia, countries with strong differences in sunlight intensity. Overall HPV seroprevalence was similar across the three countries (50-57 % for beta-HPV types, 40-48 % for gamma-HPV types), and the most frequent beta-HPV and gamma-HPV types were the same in all countries. The highest seroprevalences for 24 of the 26 skin HPV types were observed in Italy (14 types) and Australia (ten types). Seroprevalence among men was generally higher than among women, and the male sex was significantly associated with both beta-HPV [odds ratio (OR) 2.81, 95 % confidence interval (CI) 1.64-4.82] and gamma-HPV (OR 2.42, 95 % CI 1.40-4.18) antibodies in Australia. The only measure of sun sensitivity or UV exposure significantly associated with skin HPV seroprevalence was found for weekend sun exposure in Australia and beta-HPV antibodies. It was concluded that type spectra and HPV seroprevalence are similar in countries with different sunlight intensity, and that levels of UV exposure do not play a strong role in the development of skin HPV antibodies in this study population.

Case–control Study of Merkel Cell Polyomavirus Infection and Cutaneous Squamous Cell Carcinoma

Background: Merkel cell polyomavirus (MCV) DNA has been reported in 0% to 25% of squamous cell carcinomas (SCC) occurring in immunocompetent individuals. We conducted the first serologic case–control study of MCV and SCC. Methods: Patients with histologically confirmed cutaneous SCC (n = 173) were recruited from a university dermatology clinic. Controls were individuals who screened negative for and had no history of skin or other cancers (n = 300). Levels of antibodies against capsid antigens for MCV and another polyomavirus, JC virus (JCV), were determined by fluorescent bead-based multiplex serology. Fresh-frozen tumor tissues were obtained from 145 SCC cases and tested for MCV DNA by multiplexed PCR. Associations between MCV seroreactivity and SCC were estimated by ORs and 95% CIs calculated using logistic regression with adjustment for age and sex. Results: MCV DNA was detected in SCC tumor tissues from 55 (38%) of 145 cases. A statistically significant association was observed between MCV seropositivity and MCV DNA-positive SCC (OR = 2.49, 95% CI = 1.03–6.04), with an almost four-fold association observed when comparing those with MCV antibodies in the fourth versus first quartiles (OR = 3.93, 95% CI = 1.43–10.76, Ptrend = 0.01). No significant associations were observed between MCV seropositivity and MCV DNA-negative SCC (OR = 1.38, 95% CI = 0.76–2.48) or between JCV seropositivity and MCV DNA-positive or DNA-negative SCC. Conclusion: Past exposure to MCV may be a risk factor for SCC. Impact: Understanding the role of viral infections in the development of nonmelanoma skin cancer could lead to novel prevention strategies. Cancer Epidemiol Biomarkers Prev; 21(1); 74–81. ©2011 AACR.

Prospective Study of Human Papillomavirus Seropositivity and Risk of Nonmelanoma Skin Cancer

Cutaneous human papillomaviruses (HPVs) have been associated with squamous cell carcinoma (SCC) in case-control studies, but there are limited data from prospective studies assessing whether virus exposure predicts risk of future cancer development. Two major biobanks, the Southern Sweden Microbiology Biobank (1971-2003) and the Janus Biobank (1973-2003) in Norway, containing samples from 850,000 donors, were searched for incident skin cancer for up to 30 years using registry linkages. Altogether, 2,623 donors with samples taken before diagnosis of SCC or basal cell carcinoma (BCC) of the skin were identified. Prediagnostic samples and samples from 2,623 matched controls were tested for antibodies against 33 types of HPV. Baseline seropositivity to HPV types in genus β species 2 was associated with SCC risk (odds ratio = 1.3, 95% confidence interval: 1.1, 1.7); this was also the case for samples taken more than 18 years before diagnosis (odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). Type-specific persistent seropositivity entailed elevated point estimates for SCC risk for 29 HPV types and decreased point estimates for only 3 types. After multiple hypothesis adjustment, HPV 76 was significantly associated with SCC risk and HPV 9 with BCC risk. In summary, seropositivity for certain HPV types was associated with an increased risk for future development of SCC and BCC.