Cutaneous viral infections associated with ultraviolet radiation exposure.

The complex interplay between ultraviolet radiation (UVR) and cutaneous viral infections in the context of cancer etiology is challenging to unravel, given the limited information on the independent association between UVR and cutaneous viral infections. Using multiple biomarkers of infection with 24 types of cutaneous human papillomavirus (HPV) and 4 types of polyomaviruses (HPyV), we investigated cross-sectional associations with recent UVR exposure, using skin pigmentation measured by spectrophotometer. Age- and sex-adjusted associations between UVR and viral seropositivity, viral DNA present in eyebrow hairs (EBH) and skin swabs (SSW) were estimated using logistic regression. Beta-HPV seropositivity was associated with viral DNA positivity in EBH (OR = 1.40, 95% CI = 1.05-1.88) and SSW (OR = 1.86, 95% CI = 1.25-2.74). Similar associations were observed for Merkel cell polyomavirus. Participants in the highest tertile of UVR exposure were more likely to be seropositive for beta-HPV (OR = 1.81, 95% CI = 1.16-2.38), and have beta-HPV DNA in EBH (OR = 1.57, 95% CI = 1.06-2.33) and SSW (OR = 2.22, 95% CI = 1.25-3.96), compared to participants with the lowest tertile of UVR exposure. UVR exposure was positively associated with three different markers of beta-HPV infection. Therefore, future studies of HPV associated KC development should address more directly the role of HPV and UVR exposure as potential co-carcinogens.

[Merkel cell carcinoma: a highly aggressive tumor with possible viral etiology]. / Merkel-Zell-Karzinom: Ein hochaggressiver Tumor mit möglicher viraler Genese.

Merkel cell carcinoma (MCC) or neuroendocrine carcinoma of the skin, is a rare and highly aggressive tumor which typically develops in chronically sun-damaged skin in aged or immunosuppressed patients. The clinical course is characterized by early local recurrence and lymphatic metastases. The current discussion on the etiology of MCC is dominated by the recently discovered Merkel cell polyoma virus (MCPyV). Apparently, MCPyV infection takes place early in life and the virus can also be found in healthy tissue. Possibly, a mutation of the viral genome is responsible for the development of the tumor. The 5 year survival rate of patients with primary MCC is only 30-40% after surgical therapy alone but can increase to about 75% after additional adjuvant radiotherapy. In cases with lymphatic or distant metastases various chemotherapy protocols in addition to operative and radiation therapy analogous to those for small cell lung cancer therapy have been found to be effective. Nevertheless, very high recurrence rates are typical in patients with distant metastases. Thus, MCC is regarded as chemosensitive but not chemocurable.Patients with MCC should be treated with an aggressive but individually adapted concept. The consequent integration of radiotherapy into the therapeutic approach can improve the prognosis.

[Merkel cell carcinoma revisited: a new example of viro-induced human tumour]. / Le carcinome à cellules de Merkel revisité : un nouvel exemple de tumeur humaine viro-induite.

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma of the skin of poor outcome. A new type of virus, isolated in 2008, was found to be strongly associated with CCM. This virus, belonging to the family of polyomavirus, was called MCPyV for Merkel Carcinoma Polyomavirus. Recent data favour a causative role of MCPyV in oncogenesis. MCC represents thus a new model for the understanding of the mechanisms of oncogenesis. The distinct molecular viral signature in every case of MCC represents an original tool for the follow-up of the disease. New therapeutic perspectives are to be drawn using this model.

Beta-papillomavirus infection and skin cancer.

The development of highly sensitive PCR techniques and multiplex bead-based Luminex platforms has accelerated the search for a specific role of human papilloma viruses in the development of squamous cell carcinoma. Human papillomaviruses are most likely indirectly involved in this process by facilitating UV-related carcinogenesis via preventing UV-induced apoptosis or impairing DNA repair, but other mechanisms are also possible.

Genetic analysis of cutaneous squamous cell carcinomas arising from different areas.

Although cutaneous squamous cell carcinomas (SCC) occur most frequently in sun-exposed areas of the skin, they can also arise in non-sun-exposed areas. Some risk factors for cutaneous SCC, such as ultraviolet (UV) light, are well known. However, the major factor for carcinogenesis may depend on the site of the tumor as well as the ethnicity of the patient. In this study we examined 41 Japanese cutaneous SCC cases, focusing on the area of appearance and the presence of genetic alteration, with 27 cases from sun-exposed areas, 10 from non-sun-exposed areas (excluding genital areas), and four from burn scars from sun-exposed areas. Squamous cell carcinomas arising in sun-exposed areas showed less frequent p53 gene mutations compared to SCC arising in non-sun-exposed areas. Ultraviolet light-specific mutations were found in only two cases of SCC from sun-exposed areas. Human papilloma virus (HPV) DNA was detected in two cases (7.4%) of the sun-exposed areas and none of the non-sun-exposed or scar areas. The frequency of loss of heterozygosity on D5S178 in non-sun-exposed SCC was significantly higher than in sun-exposed SCC. Furthermore, the incidence of fractional allelic loss (FAL) was significantly higher in non-sun-exposed SCC than in sun-exposed SCC. Our findings suggest that sun-exposed SCC in Japan may be relatively less involved with p53 mutation, and that non-sun-exposed SCC acquire more genetic alterations than sun-exposed SCC.

Clonal chromosomal aberrations in simian virus 40-transfected human thyroid cells and in derived tumors developed after in vitro irradiation.

In vitro model cell systems are important tools for studying mechanisms of radiation-induced neoplastic transformation of human epithelial cells. In our study, the human thyroid epithelial cell line HTori-3 was analyzed cytogenetically following exposure to different doses of alpha- and gamma-irradiation and subsequent tumor formation in athymic nude mice. Combining results from G-banding, comparative genomic hybridization, and spectral karyotyping, chromosome abnormalities could be depicted in the parental line HTori-3 and in nine different HTori lines established from the developed tumors. A number of chromosomal aberrations were found to be characteristic for simian virus 40 immortalization and/or radiation-induced transformation of human thyroid epithelial cells. Common chromosomal changes in cell lines originating from different irradiation experiments were loss of 8q23 and 13cen-q21 as well as gain of 1q32-qter and 2q11.2-q14.1. By comparison of chromosomal aberrations in cell lines exhibiting a different tumorigenic behavior, cytogenetic markers important for the tumorigenic process were studied. It appeared that deletions on chromosomes 9q32-q34 and 7q21-q31 as well as an increased copy number of chromosome 20 were important for the tumorigenic phenotype. A comparative breakpoint analysis of the marker chromosomes found and those observed in radiation-induced childhood thyroid tumors from Belarus revealed a coincidence for a number of chromosome bands. Thus, the data support the usefulness of the established cell system as an in vitro model to study important steps during radiation-induced malignant transformation in human thyroid cells.

E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage.

In addition to their role in anogenital cancer, human papillomaviruses (HPVs) are also involved in the development of a range of cutaneous lesions. HPV types 5 and 8 are associated with the development of skin cancers in individuals with Epidermodysplasia verruciformis (EV). A broad spectrum of HPV types are also commonly found in non-melanoma skin cancers in immunocompromised individuals, such as organ transplant recipients. The skin cancers in EV and immunocompromised patients occur predominantly at body sites exposed to ultra violet (UV) radiation, pointing to a key role for UV in their development. Here we show that the E6 protein from a range of cutaneous HPV types effectively inhibits apoptosis in response to UV damage. This occurs in both p53 null and wild type cells and does not require p53 degradation.

The promoter of a novel human papillomavirus (HPV77) associated with skin cancer displays UV responsiveness, which is mediated through a consensus p53 binding sequence.

An aetiological role has been proposed for human papillomavirus (HPV) in skin carcinogenesis within the immunosuppressed patient population. To examine this possibility, we have focused on an HPV type that, to date, has been identified only in the cutaneous lesions of renal transplant recipients despite a high degree of sequence homology with other HPVs commonly found in warts in the general population. We report that the non-coding region of this virus, HPV type 77, contains a consensus binding site for the tumour suppressor protein p53, and we show by gel-retardation analysis that this sequence does indeed bind p53. Furthermore, using reporter gene assays, we demonstrate that HPV77 promoter activity is stimulated by UV radiation and that this response is mediated through the p53 binding site. This is the first report of a p53-dependent positive response element within a viral genome. Our results suggest a possible novel mechanism by which specific types of HPV might act as cofactors with UV radiation in cutaneous transformation.

Functional inactivation of p53 by HPV-E6 transformation is associated with a reduced expression of radiation-induced potentially lethal damage.

PURPOSE: To examine the effect of functional loss of p53 on radiation sensitivity and potentially lethal damage repair (PLDR). MATERIALS AND METHODS: Radiation sensitivity and PLDR were examined in an isogenic pair of human tumour cell lines created by HPV-E6 transformation. RESULTS: Inactivation of p53 by E6 transformation resulted in a cell line that was more resistant to killing by radiation but showed little enhancement in survival (PLDR) when plateau-phase cells were held non-cycling after radiation exposure. Holding p53-normal cells in plateau-phase after radiation exposure not only led to enhanced survival, but also to a reduction in the proportion of cells that blocked in G1 subsequent to release. CONCLUSIONS: These results suggest that p53 expression influences that component of radiation sensitivity associated with PLDR.

A new immunobiological view of radiation-promoted lymphomagenesis.

Whole-body irradiation produces T-cell leukaemias/ lymphomas (TCL) in some strains of inbred mice in an X-ray dose-related manner. Radiation biologists have related the rapid "initiation' and early appearance of preleukaemic cells in these mice to unrepaired DNA damage inflicted by radiation. Following initiation, radiation-altered thymic differentiation fosters multi-step transformation changes in proto-oncogenes and suppressor gene expression in individual clones of non-invasive preleukaemia cells as they progress to malignancy. The malignant clones arising from small numbers of initiated preleukaemia thymocytes become fully transformed only after several more months to a year after irradiation in those strains of mice which develop T-cell lymphomas. When the RFM mouse was subjected to sublethal whole-body X-ray, only 50% of the mice developed TCL by 6 months, yet nearly all developed preleukaemia thymocytes. The T-cell-mediated immune response of the irradiated host has never been substantiated to contribute to malignant TCL development. Until recently, X-ray-induced TCL were not known to carry common tumour rejection antigens TATA. However, several studies have revealed that both preleukaemia cells and fully malignant TCL express an immunogenic, common oncofoetal glycoprotein, termed 44kD OFA. OFA-activated memory CD4 Tm and CD8 Ten. T-effector cells in irradiated mice expressing OFA. As most irradiated RFM mice exhibit preleukaemia thymocytes yet only half develop tumours, this finding implicates active host T-cell effector responses in X-ray-initiated tumorigenesis. Further, the recent discovery of OFA-specific CD8 Ts clones in irradiated mice, which inhibited cytotoxicity of CD8 clones to OFA or TSTA, may explain which mice develop T-cell lymphomas.