Epidermodysplasia Verruciformis Human Papillomavirus Types Research Articles

Detection of Human Papillomavirus DNA in Cutaneous Squamous Cell Carcinoma among Immunocompetent Individuals

The presence of certain types of human papillomavirus (HPV) is a known risk factor for the development of anogenital squamous cell carcinomas (SCCs). A similar association has been hypothesized for cutaneous SCCs, although, to our knowledge, no studies to date have combined sensitive HPV DNA detection techniques with epidemiologic data controlling for known risk factors to explore the association. We designed a case-control study examining HPV prevalence using highly sensitive PCR-detection assays in tissue samples from 85 immunocompetent patients with histologically confirmed SCCs and 95 age-matched individuals without a prior history of skin cancer. A standardized interview was administered to all study subjects to collect information pertaining to potential confounding variables. The overall detection rate of HPV DNA was high in case lesions (54%) and perilesions (50%) and in both sun-exposed normal tissue (59%) and non-sun-exposed normal tissue (49%) from controls. In comparing case tissue to control tissue, there was no differential detection of HPV DNA across various HPV species. However, HPV DNA from beta-papillomavirus species 2 was more likely to be identified in tumors than in adjacent healthy tissue among cases (paired analysis, odds ratio=4.0, confidence interval=1.3-12.0). The high prevalence of HPV DNA detected among controls suggests that HPV DNA is widely distributed among the general population. However, the differential detection of HPV beta-papillomavirus species in tumors among cases suggests that certain HPV types may be involved in the progression of cutaneous SCCs.

Skin human papillomavirus type 38 alters p53 functions by accumulation of ΔNp73

The E6 and E7 of the cutaneous human papillomavirus (HPV) type 38 immortalize primary human keratinocytes, an event normally associated with the inactivation of pathways controlled by the tumour suppressor p53. Here, we show for the first time that HPV38 alters p53 functions. Expression of HPV38 E6 and E7 in human keratinocytes or in the skin of transgenic mice induces stabilization of wild-type p53. This selectively activates the transcription of deltaNp73, an isoform of the p53-related protein p73, which in turn inhibits the capacity of p53 to induce the transcription of genes involved in growth suppression and apoptosis. DeltaNp73 downregulation by an antisense oligonucleotide leads to transcriptional re-activation of p53-regulated genes and apoptosis. Our findings illustrate a novel mechanism of the alteration of p53 function that is mediated by a cutaneous HPV type and support the role of HPV38 and deltaNp73 in human carcinogenesis.

Human Papillomavirus Gene Expression in Cutaneous Squamous Cell Carcinomas from Immunosuppressed and Immunocompetent Individuals

Epidermodysplasia verruciformis (EV)-type human papillomavirus (HPV) DNA have been detected by PCR in squamous cell carcinomas (SCC) from both organ transplant recipients (OTR) and immunocompetent individuals. Their role in skin cancer remains unclear, and previous studies have not addressed whether the viruses are transcriptionally active. We have used in situ hybridization to investigate the transcriptional activity and DNA localization of HPV. EV-HPV gene transcripts were demonstrated in four of 11 (36%) OTR SCC, one of two (50%) IC SCC, and one of five (20%) OTR warts positive by PCR. Viral DNA co-localized with E2/E4 early region gene transcripts in the middle or upper epidermal layers. Non-EV cutaneous HPV gene transcripts were demonstrated in one of five (20%) OTR SCC and four of 10 (40%) OTR warts. In mixed infections transcripts for both types were detected in two of six (33%) cases. Our results provide evidence of EV-HPV gene expression in SCC; although only a proportion of tumors were positive, the similarly low transcriptional activity in warts suggests this is an underestimate. These observations, together with emerging epidemiological and functional data, provide further reason to focus on the contribution of EV-HPV types to the pathogenesis of cutaneous SCC.

TP53 mutations in squamous-cell carcinomas of the conjunctiva: evidence for UV-induced mutagenesis.

Squamous cell carcinoma of the conjunctiva is associated with sun exposure and often occurs in HIV-positive individuals. We have analysed TP53 mutations in 21 cases of squamous cell carcinoma and 22 controls with benign conjunctival lesions from a region (Uganda, Africa) with a high prevalence of heavy sun exposure and HIV infection. TP53 mutations were detected in 11 cases (52%) and 3 controls (14%). Seven of the mutations (6 in cases and 1 in controls) were CC-->TT transitions, a molecular signature of mutagenesis by solar UV rays. A similar prevalence (56%) of TP53 mutations was found in 18 squamous cell carcinoma cases positive for epidermodysplasia verruciformis human papillomavirus types. The prevalence of CC-->TT transitions reported here is the highest observed in any cancer type and matches that of skin cancers in subjects with xeroderma pigmentosum, an inherited disease with hypersensitivity to UV damage. These results confirm at the molecular level the causal role of solar UV rays in the aetiology of squamous cell carcinoma of the conjunctiva and suggest that infection with epidermodysplasia verruciformis types of human papillomavirus may act as a cofactor to increase the sensitivity of conjunctiva cells to UV-induced mutagenesis.

Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin.

Human papillomaviruses (HPVs) are found in normal skin and in benign and malignant skin conditions. Epidermodysplasia verruciformis (EV) HPV types are those most plausibly linked to the development of squamous cell carcinomas of the skin. To assess the risk of nonmelanoma skin cancer (NMSC) associated with the presence of EV HPV in normal skin in immunocompetent (IC) individuals and renal transplant recipients (RTRs). Using a degenerate and nested polymerase chain reaction technique, HPV DNA was sought in 124 normal skin samples from sun-exposed and nonsun-exposed sites, from 39 IC individuals and 38 RTRs, both with and without NMSC. Data were analysed using the Mantel-Haenszel test and by logistic regression analysis. HPV DNA was detected in 58/67 (87%) and 20/57 (35%) samples from renal transplant and IC patients, respectively. There was no difference in either the prevalence or spectrum of HPV types found in sun-exposed and nonsun-exposed normal skin. However, there was significant association between NMSC and the presence of EV HPV DNA. Multivariate analysis provided an odds ratio of 6.41 (95% confidence interval 1.79-22.9) for the association of EV HPV DNA in normal skin (irrespective of site) and NMSC status, even after stratifying for patient group and adjusting for the clustering effect of multiple sampling. Conversely, there was no association between skin cancer status and the presence of cutaneous or mucosal HPV types in either sun-exposed or nonsun-exposed skin. HPV DNA is widespread in normal adult skin, particularly in transplant patients. In our study, the presence of EV but not cutaneous HPV DNA in normal skin was significantly associated with NMSC status and may prove to be of predictive value for skin cancer risk. These data provide reason to focus on EV HPV types as causal agents in skin cancer.

Epidermodysplasia verruciformis human papillomavirus types and carcinoma of the conjunctiva: a pilot study.

A total of 21 squamous-cell carcinoma of the conjunctiva (SCC) and 22 control subjects had conjunctival samples tested for human papillomavirus (HPV) types using PCR-based assays. Epidermodysplasia verruciformis HPV types were found in 86% of SCC cases and 36% of control subjects (Odds ratio=12.0), suggesting a role of HPVs in the aetiology of SCC.

Epidermodysplasia verruciformis human papillomavirus types are frequently detected in skin lesions associated with HIV infection

Human papillomavirus (HPV) is one of the more common viral causes of mucocutaneous lesions in HIV positive individuals. The incidence of cutaneous warts in adult and paediatric HIV infection is estimated to be up to 27%. These warts are often multiple, large, rapidly growing, refractory to treatment, and may result in considerable morbidity. Epidermodysplasia verruciformis (EV)-like presentations have been reported and epidermal dysplasia progressing to in situ carcinoma has also been reported within the warts of HIV positive individuals. There is evidence that immune status may influence the HPV types harboured by skin lesions. However, there are relatively few studies in which the spectrum of HPV types present in HIV-associated cutaneous lesions have been analysed. In this study we present the results of HPV typing from a series of lesion from HIV infected individuals.

A broad spectrum of human papillomavirus types is present in the skin of Australian patients with non-melanoma skin cancers and solar keratosis.

Human papillomavirus (HPV) may play a role in the pathogenesis of non-melanoma skin cancer (NMSC) in epidermodysplasia verruciformis (EV) patients, but in the general population no specific HPV types have been associated with these lesions. Objectives To examine the spectrum of HPV types present in the skin and tumours of Australian patients with NMSC or solar keratosis (SK). Biopsies from tumours, and cotton swab samples of perilesional skin and buttock skin from each of 59 Australian patients with basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or SK were tested for HPV DNA by polymerase chain reaction (PCR) using HPV consensus (FAP) primers and by type-specific primers for HPV 38 and candidate HPV 92. The identification of HPV type from consensus PCR was performed by sequencing and comparison with GenBank. In total, 49 of 59 (83%) patients harboured HPV DNA, which was detected in 28 of 64 (44%) biopsies, 48 of 64 (75%; P < 0.001) perilesional swabs and 36 of 59 (61%; P = 0.04) buttock swabs. Forty-five different HPV types/putative types were detected: 15 were previously characterized HPV types, 17 were earlier described putative types and 13 were new putative types. In addition, six subtypes and four variants of HPV sequences were identified. HPV types within the B1 group (EV HPV types) were found in 26 of 64 (40%) lesions, 44 of 64 (69%) perilesional swabs and 35 of 59 (59%) buttock swabs. HPV 38 was detected in 23 of 59 (39%) patients, and was found in seven of 16 (43%) SKs, but was less common in SCCs [three of 23 (13%); P = 0.037] and BCCs [four of 25 (16%); P = 0.056]. Candidate HPV 92 was found in seven of 59 (12%) patients. A broad spectrum of HPV types, the majority from the B1 group, was found in skin of Australian patients with skin tumours. HPV 38 was found significantly more often in SK than in SCC. However, the role of cutaneous HPV infection in the pathogenesis of NMSC remains elusive.

Human papillomaviruses and non-melanoma skin cancer

Epidemiological and experimental studies have overwhelmingly confirmed human papillomaviruses as important causal agents in anogenital carcinogenesis. A role for human papillomaviruses has also been proposed in a diverse range of other malignancies, and particular interest has focused on non-melanoma skin cancer, the commonest malignancy in fair-skinned populations worldwide. Although the evidence for this is considerably less convincing than for anogenital cancer, important epidemiological and functional data have emerged over the past year that have furthered our understanding of the possible contribution of human papillomaviruses to skin cancer. Epidemiological human papillomavirus DNA detection studies have shown associations with non-melanoma skin cancer, but have also emphasized the ubiquity of epidermodysplasia verruciformis human papillomavirus types in normal skin, hair follicles and benign hyperproliferative disorders, as have seroepidemiological approaches. Functional investigations have demonstrated mechanistically relevant interactions between the virus and ultraviolet radiation, host cytokines and cellular proteins including p53 and the pro-apoptotic protein Bak. Taken together, these data have advanced our understanding of the contribution of human papillomaviruses to malignant transformation in cutaneous keratinocytes, but further research is required before a causal association between human papillomaviruses and skin cancer is reliably confirmed.

Association Between Epidermodysplasia Verruciformis-Associated Human Papillomavirus DNA in Plucked Eyebrow Hair and Solar Keratoses

Association Between Epidermodysplasia Verruciformis-Associated Human Papillomavirus DNA in Plucked Eyebrow Hair and Solar Keratoses

Case-control study in a subtropical Australian population to assess the relation between non-melanoma skin cancer and epidermodysplasia verruciformis human papillomavirus DNA in plucked eyebrow hairs. The Nambour Skin Cancer Prevention Study Group.

Epidermodysplasia verruciformis human papillomavirus (EV-HPV) DNA has been demonstrated in malignant and benign skin lesions and in hairs plucked from renal transplant recipients and immunocompetent patients. We investigated the association between EV-HPV DNA in hairs plucked from eyebrows and the occurrence of non-melanoma skin cancer (NMSC) in a community-based study. Within a cohort of residents of a Queensland township (Nambour), nested case-control studies of recently developed NMSC (64 cases), basal-cell carcinoma (BCC) (51 cases) and squamous-cell carcinoma (SCC) (25 cases) were conducted. EV-HPV DNA in hair and a small number of available tumour samples was detected using a nested PCR specific for EV-HPV types. EV-HPV DNA was detected in hairs from 94 of 143 individuals (66%), and 36 (39%) of the samples contained 2 or more different EV-HPV types. Only known or putatively new EV-HPV types were detectable after sequencing 93 samples. EV-HPV status agreed for 12 of 20 subjects who had both hair and skin tumour samples available. In 4 of 5 pairs of positive samples, the same EV-HPV type was found. There were non-significant negative associations between EV-HPV and NMSC (OR 0.77, 95% CI 0.34-1.8) and BCC (OR 0.58, 95% CI 0.23-1.5) but a non-significant positive association with SCC (OR 2.00, 95% CI 0.50-8.0).

Degenerate and nested PCR: a highly sensitive and specific method for detection of human papillomavirus infection in cutaneous warts.

The role of human papillomavirus (HPV) in anogenital carcinogenesis is firmly established, but evidence that supports a similar role in skin remains speculative. Immunosuppressed renal transplant recipients have an increased incidence of viral warts and nonmelanoma skin cancer, and the presence of HPV DNA in these lesions, especially types associated with the condition epidermodysplasia verruciformis (EV), has led to suggestions that HPV may play a pathogenic role. However, differences in the specificities and sensitivities of techniques used to detect HPV in skin have led to wide discrepancies in the spectrum of HPV types reported. We describe a degenerate nested PCR technique with the capacity to detect a broad spectrum of cutaneous, mucosal, and EV HPV types. In a series of 51 warts from 23 renal transplant recipients, this method detected HPV DNA in all lesions, representing a significant improvement over many previously published studies. Cutaneous types were found in 84.3% of warts and EV types were found in 80.4% of warts, whereas mucosal types were detected in 27.4% of warts. In addition, the method allowed codetection of two or more distinct HPV types in 94.1% of lesions. In contrast, single HPV types were detected in all but 1 of 20 warts from 15 immunocompetent individuals. In summary, we have established a highly sensitive and comprehensive degenerate PCR methodology for detection and genotyping of HPV from the skin and have demonstrated a diverse spectrum of multiple HPV types in cutaneous warts from transplant recipients. Studies designed to assess the significance of these findings to cutaneous carcinogenesis are under way.

Detection and typing of human papillomaviruses in mucosal and cutaneous biopsies from immunosuppressed and immunocompetent patients and patients with epidermodysplasia verruciformis: a unified diagnostic approach.

AIM: To develop a unified diagnostic approach for the detection of human papillomavirus (HPV) DNA in skin and mucosal biopsies from both immunocompetent and immunosuppressed individuals using a degenerate polymerase...

Detection of Human Papillomavirus DNA in PUVA-Associated Non-Melanoma Skin Cancers

Psoralen and UVA (PUVA) photochemotherapy is associated with a dose-dependent increased risk of nonmelanoma skin cancer in patients treated for psoriasis. Like ultraviolet B radiation, PUVA is both mutagenic and immunosuppressive and may thus act as a complete carcinogen; however, the reversed squamous to basal cell carcinoma ratio (SCC:BCC) in PUVA-treated patients, also seen in immunosuppressed renal transplant recipients, suggests a possible cofactor role for human papillomavirus (HPV) infection. In this study we examine a large series of benign and malignant cutaneous lesions for the presence of HPV DNA from patients treated with high dose (> or =500 J per cm2) ultraviolet A. A panel of degenerate primers based on the L1 (major capsid protein) open reading frame was employed, designed to detect mucosal, cutaneous, and epidermodysplasia verruciformis HPV types with high sensitivity and specificity. HPV DNA was detected in 15 of 20 (75%) non-melanoma skin cancer, seven of 17 (41.2%) dysplastic PUVA keratoses, four of five (80%) skin warts, and four of 12 (33%) PUVA-exposed normal skin samples. The majority of HPV positive lesions contained epidermodysplasia verruciformis-related HPV including HPV-5, -20, -21, -23, -24, and -38. Possible novel epidermodysplasia verruciformis types were identified in further lesions. Mixed infection with epidermodysplasia verruciformis, cutaneous, and/or mucosal types was present in six of 30 (20%) of all HPV positive lesions, including in normal skin, warts, dysplastic PUVA keratoses, and squamous cell carcinomas. The prevalence and type of HPV infection in cutaneous lesions from PUVA-treated patients is similar to that previously reported in renal transplant-associated skin lesions, and suggests that the role of HPV in PUVA-associated carcinogenesis merits further study.

Prevailing papillomavirus types in non-melanoma carcinomas of the skin in renal allograft recipients

The role of human papillomavirus (HPV) in the aetiology of in situ and invasive carcinoma of the genital tract is well established. In the rare disorder epidermodysplasia verruciformis (EV), in which patients develop extensive warts of unusual types and multiple cutaneous squamous cancers on light-exposed skin, current evidence suggests a probable role for a specific group of EV HPVs in the carcinogenic process. Determination of the possible role of HPV in the aetiology of non-melanoma skin cancers (NMSCs), which occur frequently in immunosuppressed organ allograft recipients, has been limited, until recently, by the lack of availability of a sensitive detection system for a wide range of cutaneous HPV types. We have used a combination of 2 sets of PCR primers to examine 68 benign and malignant tumours collected over a 12-year period from 25 renal allograft recipients. Cloning and sequencing of the PCR products were carried out to distinguish HPV DNA from cellular sequences. A combination of these techniques revealed HPV DNA in all viral warts, 65% of keratoses, 91% of intra-epidermal cancers and 91% of invasive squamous cancers. Both cutaneous and EV HPV types were detected, including 18 novel types. In 4 patients with multiple cancers, the most prevalent types were in the EV group: HPV 20, 23, 38 and 2 novel types, DL40 and DL267 (related to HPV 10 and 38, respectively). These 5 HPV types were present in a total of 73% of all malignant lesions tested. The technique described represents a reliable method of HPV DNA detection in NMSC. The EV group of HPVs predominate in the cancers, but the multiplicity of HPV types detected with double infection in some lesions suggests virus/virus in addition to virus/host interaction in the carcinogenic process.