Evidence suggests that beta human papillomaviruses (HPVs), together with ultraviolet radiation, contribute to the development of cutaneous squamous cell carcinoma. Beta HPVs appear to be not the main drivers of carcinogenesis but rather facilitators of the accumulation of ultraviolet-induced DNA mutations. Beta HPVs are promoters of skin carcinogenesis, although they are dispensable for the maintenance of the malignant phenotype. Therefore, beta HPV represents a target for skin cancer prevention, especially in high-risk populations. KEYWORDS UV radiation, human papillomavirus, skin cancer T he human papillomavirus (HPV) family comprises approximately 200 types that are able to infect the mucosal and cutaneous epithelia (1). They are subdivided into genera and species in the HPV phylogenetic tree according to the DNA sequence of the late gene L1 (2). The genus Alphapapillomavirus includes the mucosal high-risk (HR) HPV types that have been clearly associated with the development of cervical and anal cancers and a subset of other genital tract cancers, such as vulvar, vaginal, and penile carcinomas, as well as a subset of head and neck cancers (3). More than 40 years of research have elucidated many of the HR HPV mechanisms involved in cancer development. The products of two early genes, E6 and E7, are major oncoproteins able to deregulate many key cellular events and greatly facilitate the malignant transformation of the infected cells. Classic examples of processes targeted by HR HPV E6 and/or E7 oncoproteins are the cell cycle, DNA repair, apoptosis, senescence, and the immune response (4). In the context of the viral life cycle, these activities of E6 and E7 are essential to guarantee viral DNA replication and progeny production. As a side effect, they facilitate the accumulation of chromosomal abnormalities, leading to cancer development. Despite the accumulation of this DNA damage, constant expression of the viral oncogenes is required for the maintenance of the transformed phenotype. Indeed, experiments in in vitro models have shown that silencing of E6 and E7 expression in cervical cancer-derived cell lines, such as CaSki or HeLa, severely affects cell viability (5-8). Because of the biological properties of the HR HPV E6 and E7 in directly targeting several cellular proteins/pathways, HPV-positive cancer cells do not usually accumulate many mutations compared with cancers associated with other environmental factors. For instance, HPV-negative oropharyngeal cancers have more DNA mutations, which are often linked to tobacco use and/or alcohol consumption, compared with HPV-positive oropharyngeal cancers (9).Similar to the HR HPV types, cutaneous beta HPV types have also been implicated in carcinogenesis, although the model of carcinogenesis is quite different. Epidemiological and biological studies support the model of synergistic cooperation between Citation Rollison DE, Viarisio D, Amorrortu RP, Gheit T, Tommasino M. 2019. An emerging issue in oncogenic virology: the role of beta human papillomavirus types...

BackgroundDespite efforts to increase diversity in clinical trials, racial/ethnic minority groups generally remain underrepresented, limiting researchers’ ability to test the efficacy and safety of new interventions across diverse populations. We describe the use of a systematic framework, intervention mapping (IM), to develop an intervention to modify recruitment behaviors of coordinators and specialist investigators with the goal of increasing diversity in trials conducted within specialty clinics. To our knowledge IM has not been used in this setting.MethodsThe IM framework was used to ensure that the intervention components were guided by health behavior theories and the evidence. The IM steps consisted of (1) conducting a needs assessment, (2) identification of determinants and objectives, (3) selection of theory-informed methods and practical applications, (4) development and creation of program components, (5) development of an adoption and implementation plan, and (6) creation of an evaluation plan.ResultsThe intervention included five educational modules, one in-person and four web-based, plus technical assistance calls to coordinators. Modules addressed the intervention rationale, development of clinic-specific plans to obtain minority-serving physician referrals, physician-centered and patient-centered communication, and patient navigation. The evaluation, a randomized trial, was recently completed in 50 specialty clinics and is under analysis.ConclusionsUsing IM we developed a recruitment intervention that focused on building relationships with minority-serving physicians to encourage minority patient referrals. IM enhanced our understanding of factors that may influence minority recruitment and helped us integrate strategies from multiple disciplines that were relevant for our audience.

Background Racial/ethnic minority groups remain underrepresented in clinical trials. Many strategies to increase minority recruitment focus on minority communities, and emphasize common diseases such as hypertension. Scant literature focuses on minority recruitment to trials of less common conditions, often conducted in specialty clinics, and dependent on physician referrals. We identified trust/mistrust of specialist physician investigators and institutions conducting medical research and consequent participant reluctance to participate in clinical trials as key-shared barriers across racial/ethnic groups. We developed a trust-based continuous quality improvement (CQI) intervention to build trust between specialist physician investigators and community minority-serving physicians and ultimately potential trial participants. To avoid the inherent biases of non-randomized studies, we evaluated the intervention in the national Randomized Recruitment Intervention Trial (RECRUIT). This report presents the design of RECRUIT. Specialty clinic follow-up continues through April 2017. Methods We hypothesized that specialist physician investigators and coordinators trained in the trust-based CQI intervention would enroll a greater proportion of minority participants in their specialty clinics than specialist physician investigators in control specialty clinics. Specialty clinic was the unit of randomization. Using CQI, the specialist physician investigators and coordinators tailored recruitment approaches to their specialty clinic characteristics and populations. Primary analyses were adjusted for clustering by specialty clinic within parent trial and matching covariates. Results RECRUIT was implemented in four multi-site clinical trials (parent trials) supported by three NIH Institutes and included 50 associated specialty clinics from these parent trials. Using current data, we have 88% power or greater to detect a 0.15 or greater difference from the currently observed control proportion adjusting for clustering. We detected no differences in baseline matching criteria between intervention and control specialty clinics (all p-values >0.17). Conclusions RECRUIT was the first multi-site randomized control trial to examine the effectiveness of a trust-based CQI intervention to increase minority recruitment into clinical trials. RECRUIT’s innovations included its focus on building trust between specialist investigators and minority-serving physicians, the use of CQI to tailor the intervention to each specialty clinic’s specific racial/ethnic populations and barriers to minority recruitment, and the use of specialty clinics from more than one parent multi-site trial to increase generalizability. The effectiveness of the RECRUIT intervention will be determined after the completion of trial data collection and planned analyses.

UV radiation (UVR) causing DNA damage is a well-documented risk factor for nonmelanoma skin cancer. Although poorly understood, UVR may also indirectly contribute to carcinogenesis by promoting immune evasion. To our knowledge, we report the first epidemiological study designed to investigate the association between quantitative measures of UVR, obtained using a spectrophotometer, and circulating T regulatory (Treg) cells. In addition to total Treg cells, the proportion of functionally distinct Treg cell subsets defined by CD45RA and CD27 phenotypic markers, graded expression of FOXP3 and CD25, and those expressing cutaneous lymphocyte–associated Ag and the chemokine receptor CCR4 were enumerated in 350 individuals undergoing routine skin cancer screening exams and determined not to have prevalent skin cancer. No associations were identified for UVR exposure or the overall proportion of circulating Treg cells; however, Treg cell subpopulations with an activation-associated phenotype, CD45RA−/CD27−, and those expressing cutaneous homing receptors were significantly positively associated with UVR. These subpopulations of Treg cells also differed by age, sex, and race. After stratification by natural skin tone, and adjusting for age and sex, we found that spectrophotometer-based measures of UVR exposure, but not self-reported measures of past sun exposure, were positively correlated with the highest levels of these Treg cell subpopulations, particularly among lighter-skinned individuals. Findings from this large epidemiologic study highlight the diversity of human Treg cell subpopulations associated with UVR, thus raising questions about the specific coordinated expression of CD45RA, CD27, CCR4, and cutaneous lymphocyte–associated Ag on Treg cells and the possibility that UVR contributes to nonmelanoma skin cancer carcinogenesis through Treg cell–mediated immune evasion.

The cutaneous human papillomavirus (HPV), mostly from β- and γ-HPV genus, is ubiquitously distributed throughout the human body and may be part of the commensal flora. The association of β-HPVs and cutaneous squamous cell carcinoma (cSCC) development was initially reported in patients with the rare genetic disorder Epidermodysplasia verruciformis. Likewise, immunosuppressed organ transplant recipients have an increased susceptibility to β-HPV infections in the skin as well as to cSCC development. Although ultraviolet radiation (UVR) is the main risk factor of cSCC, experimental data points toward β-HPVs as co-carcinogens, which appear to be required solely at early stages of skin carcinogenesis by facilitating the accumulation of UVR-induced DNA mutations. Several epidemiological studies relying on different biomarkers of β-HPV infections have also been conducted in immunocompetent individuals to access their association with cSCC development. Additionally, in vivo and in vitro studies are presenting cumulative evidence that E6 and E7 proteins from specific β-HPVs exhibit transforming activities and may collaborate with different environmental factors in promoting carcinogenesis. Nevertheless, further research is crucial to better understand the pathological implications of the broad distribution of these HPVs.

Introduction-Accumulating evidence suggests that cutaneous viral infections are risk factors for the development of keratinocyte carcinomas (KC). The Viruses in Skin Cancer (VIRUSCAN) Study, a prospective cohort study, was established in 2014 to investigate the risk of KC associated with cutaneous human papillomavirus and polyomavirus infection and the possible interaction with ultraviolet radiation exposure (UVR).Methods/Results-VIRUSCAN incorporates repeated measures of viral infection using multiple markers of infection and quantitative measures of UVR using a spectrophotometer. Participants were recruited between July 14, 2014-August 31, 2017 at the University of South Florida Dermatology Clinic in Tampa, FL. After excluding 124 individuals with prevalent KC at baseline, 1,179 participants (53.2% women, 46.8% men, all ages 60 years and older) were followed for up to four years with routine skin exams occurring every 6-12 months. Here we present the VIRUSCAN Study design, methods and baseline characteristics including demographics, sun exposure behavior, quantitative UVR exposure measurements and cutaneous viral prevalence for the full study cohort. Conclusions-The VIRUSCAN Study will provide critical temporal evidence needed to assess the causality of the role cutaneous viral infections play in the development of KC, as well as the potential interaction between cutaneous viral infections and UVR exposure.

Background. Findings from previous studies of cutaneous human papillomavirus (cuHPV) infection and keratinocyte carcinomas have varied due to several factors, including use of different sample types for cuHPV DNA detection. Elucidating the relationship between cuHPV infection in eyebrow hairs (EBHs) and skin swabs (SSWs) is critical for advancing the design of future studies. Methods. DNA corresponding to 46 β-HPV and 52 γ-HPV types was measured in EBHs and SSWs obtained from 370 individuals undergoing routine skin cancer screening examinations. Results. Prevalence of β-HPV/γ-HPV was 92%/84% and 73%/43% in SSWs and EBHs, respectively, with 71%/39% of patients testing positive for β-HPV/γ-HPV in both sample types. Number of cuHPV types detected and degree of infection were correlated across SSWs and EBHs. When the EBH was positive for a given β-HPV/γ-HPV type, the SSW was positive for that same type 81%/72% of the time. Conclusions. Testing SSWs captures more cuHPV infection than EBHs, with EBH infections usually representing a subset of SSW infections. The importance of optimizing sensitivity of cuHPV infection detection using SSWs vs specificity using EBHs (or a combination of the 2) will be ascertained in an ongoing cohort study investigating cuHPV associations with subsequent keratinocyte carcinomas.

Cutaneous human papillomavirus (cuHPV) infections may be novel targets for skin cancer prevention and treatment, but critical information regarding the development of virus-positive skin cancers following cuHPV infection has been lacking. In this study, baseline cuHPV infection was measured by serology and viral DNA detection in eyebrow hairs (EBH) and forearm skin swabs (SSW) among 1,008 individuals undergoing routine skin cancer screening exams and followed for incidence of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cuSCC). Baseline β-HPV detection, particularly in SSW, significantly predicted cuSCC (HR = 4.32; 95% confidence interval, 1.00–18.66), whereas serologic evidence of past β-HPV infection was not associated with cuSCC. Less than 5% of baseline β-HPV types detected in SSW were present in subsequent cuSCC tumors, and cuHPV detected in SSW with higher mean fluorescence intensity values were more likely to be present in cuSCC compared with those with lower levels (P < 0.001). β-HPV-positive cuSCC occurred more often in areas of highly sun-damaged skin than did β-HPV-negative cuSCC. Overall, no clear patterns were observed between baseline β-HPV detection and subsequent development of BCC, or between baseline γ-HPV detection and either cuSCC or BCC. Collectively, these results demonstrate that β-HPV detection in SSW is a significant predictor of cuSCC risk, although evidence suggests only a small subset of cuSCC is etiologically linked to β-HPV infection. Significance: β-HPV positivity may be a useful biomarker for identifying individuals who could benefit from increased screening or novel cutaneous squamous cell carcinoma prevention strategies.