Betapapillomaviruses: Innocent bystanders or causes of skin cancer

Feltkamp, Mariet C.W.; Koning, Maurits N.C. de; Bavinck, Jan Nico Bouwes; Schegget, Jan ter

doi:10.1016/j.jcv.2008.09.009

Cited by 90 publications

(94 citation statements)

References 91 publications

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“…To date, the evidence suggesting a causal role of b-HPV in skin cancer has been tainted by: the finding that viral DNA is also found in normal skin, that discovery of the viral genome copy number is usually much less than one viral genome per tumor cell and the fact that viral transcripts have not been identified by high-throughput mRNA sequencing. 19,[54][55][56][57] Alongside the fact that ubiquitous b-HPV DNA carriage does not necessarily indicate active infection, these issues have created and so far maintained a state of uncertainty about the causative role of b-HPVs in non-epidermodysplasia verruciformis skin cancer. Although the present study does not directly demonstrate a causal role of these viruses, the detection of E4 and L1 positivity in (i) actinic keratosis, which are widely regarded to be squamous cell carcinoma precursors or in situ carcinoma, and (ii) the adjacent pathological epithelium of one squamous cell carcinoma and one basal cell carcinoma, clearly shows that b-HPV are actively replicating in the lesional skin of organ transplant recipients and can therefore cooperate with other carcinogenic agents, such as UVB, favoring skin cancer promotion and progression.…”

Section: Modern Pathology (2014) 27 1101-1115mentioning

confidence: 99%

Improved detection reveals active β-papillomavirus infection in skin lesions from kidney transplant recipients

et al. 2014

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The aim of this study was to determine whether detection of b-HPV gene products, as defined in epidermodysplasia verruciformis skin cancer, could also be observed in lesions from kidney transplant recipients alongside the viral DNA. A total of 111 samples, corresponding to 79 skin lesions abscised from 17 kidney transplant recipients, have been analyzed. The initial PCR analysis demonstrated that b-HPV-DNA was highly present in our tumor series (85%). Using a combination of antibodies raised against the E4 and L1 proteins of the b-genotypes, we were able to visualize productive infection in 4 out of 19 actinic keratoses, and in the pathological borders of 1 out of 14 squamous cell carcinomas and 1 out of 31 basal cell carcinomas. Increased expression of the cellular proliferation marker minichromosome maintenance protein 7 (MCM7), that extended into the upper epithelial layers, was a common feature of all the E4-positive areas, indicating that cells were driven into the cell cycle in areas of productive viral infections. Although the present study does not directly demonstrate a causal role of these viruses, the detection of E4 and L1 positivity in actinic keratosis and the adjacent pathological epithelium of skin cancer, clearly shows that b-HPV are actively replicating in the intraepidermal precursor lesions of kidney transplant recipients and can therefore cooperate with other carcinogenic agents, such as UVB, favoring skin cancer promotion. Modern Pathology (2014) 27, 1101-1115; doi:10.1038/modpathol.2013.240; published online 3 January 2014Keywords: b-HPV; immunosuppression; kidney transplant recipients; skin cancer; viral life cycle Solid organ transplantation is a treatment offered to an increasing number of patients with end-stage organ diseases. Although lifesaving, organ transplantation is associated with an overall three-to fivefold increased risk of malignancies. 1-4 Most of these cancers are caused by reactivated viruses whose oncogenic potential is suppressed by immunological reactions in healthy individuals, like Epstein-Barr virus-associated B-cell lymphomas, Kaposi's sarcoma, caused by the reactivation of human herpesvirus type 8, and Merkel cell carcinoma of the skin, associated with Merkel cell polyomavirus. [5][6][7][8][9] Of the cancers presenting in organ transplant recipients that have no established infectious etiology, skin cancer is the most frequent form (95%), including squamous and basal cell carcinomas. [10][11][12][13] The incidence of skin cancer, the most common cancer in fair-skinned populations, is at least 50-fold higher in organ transplant recipients. 14-16 Large numbers of skin tumors (often more than 10) tend to develop over time in these at-risk subjects, thus

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Section: Modern Pathology (2014) 27 1101-1115mentioning

confidence: 99%

Improved detection reveals active β-papillomavirus infection in skin lesions from kidney transplant recipients

et al. 2014

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“…This finding is in stark contrast to the predominance of HPV16 in the pathogenesis of cervical carcinoma. The almost ubiquitous presence of betaPV infection in eyebrow hairs, together with very low amounts of betaPV DNA in the skin (42), raises questions about appropriate markers of pathogenic infection and how betaPV could contribute to the development of cutaneous squamous cell carcinoma (43)(44)(45). In contrast to HPV16 and HPV18, the viral load in squamous cell carcinoma seldom reaches the level of 1 viral copy per cell on average (42), indicating that betaPV are not involved in maintenance of the transformed state of the tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Multicenter Study of the Association between Betapapillomavirus Infection and Cutaneous Squamous Cell Carcinoma

et al. 2010

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Human papillomaviruses (betaPV) from the beta genus cannot be classified according to their oncogenicity due to a paucity of information. This study evaluates the association between betaPV infection and cutaneous squamous cell carcinoma in conjunction with measures of UV exposure and susceptibility. We performed casecontrol studies in the Netherlands, Italy, and Australia, countries with profoundly different UV exposures. The presence of 25 betaPV types in eyebrow hair follicles was determined using a highly sensitive HPV DNA genotyping assay, and antibodies for the 15 most prevalent betaPV types in a total of 689 squamous cell carcinoma cases and 845 controls were detected using multiplex serology. Multivariate logistic regression models were used for case-control comparisons and interaction analyses. BetaPV DNA was detected in eyebrow hairs of more than 90% of all participants. The presence of betaPV DNA was associated with an increased risk of squamous cell carcinoma in the Netherlands (OR ¼ 2.8; 95% CI 1.3-5.8) and Italy (OR ¼ 1.7; 95% CI 0.79-3.6), but not in Australia (OR ¼ 0.91; 95% CI 0.53-1.6). Seropositivity for betaPV in controls ranged between 52% and 67%. A positive antibody response against 4 or more betaPV types was associated with squamous cell carcinoma in Australia (OR ¼ 2.2; 95% CI 1.4-3.3), the Netherlands (OR ¼ 2.0; 95% CI 1.2-3.4) and fair-skinned Italians (OR ¼ 1.6, 95% CI 0.94-2.7). The association between UV susceptibility and squamous cell carcinoma was stronger in betaPV-seropositive people. These combined data support the hypothesis that betaPV may play a role in the development of cutaneous squamous cell carcinoma. Cancer Res; 70(23); 9777-86. Ó2010 AACR.

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“…Mucosal HPV infections tend to clear on their own, but in some cases, latent infection could be established and may persist for years. Cutaneous ␤-genus HPV infections are highly prevalent in the general population and tend to persist (14). Vaccines based on virus-like particles made up of the capsid protein L1 have been developed against HPV-6b, -11, -16, and -18 (Cervarix [GlaxoSmithKline] and Gardasil/Silgard [Merck Research Laboratories]).…”

mentioning

confidence: 99%

Development of a Cellular Assay System To Study the Genome Replication of High- and Low-Risk Mucosal and Cutaneous Human Papillomaviruses

Geimanen

Isok-Paas

Pipitch

et al. 2011

J Virol

113

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We found that recircularized high-risk (type 16 and 18) and low-risk mucosal (type 6b and 11) and cutaneous (type 5 and 8) human papillomavirus (HPV) genomes replicate readily when delivered into U2OS cells by electroporation. The replication efficiency is dependent on the amount of input HPV DNA and can be followed for more than 3 weeks in proliferating cell culture without selection. Cotransfection of recircularized HPV genomes with a linear G418 resistance marker plasmid has allowed subcloning of cell lines, which, in a majority of cases, carry multicopy episomal HPV DNA. Analysis of the HPV DNA status in these established cell lines showed that HPV genomes exist in these cells as stable extrachromosomal oligomers. When the cell lines were cultivated as confluent cultures, a 3-to 10-fold amplification of the HPV genomes per cell was induced. Two-dimensional (2D) agarose gel electrophoresis confirmed amplification of mono-and oligomeric HPV genomes in these confluent cell cultures. Amplification occurred as a result of the initiation of semiconservative two-dimensional replication from one active origin in the HPV oligomer. Our data suggest that the system described here might be a valuable, cost-effective, and efficient tool for use in HPV DNA replication studies, as well as for the design of cell-based assays to identify potential inhibitors of all stages of HPV genome replication.Due to their association with distinctive human cancers, human papillomaviruses (HPVs) are widely studied. Papillomaviruses have been phylogenetically grouped into genera, species, types, subtypes, and variants (11), and more than 100 HPV types have been identified thus far. The best-characterized ␣-genus HPVs are associated with infections of the mucosal epithelia that lead to the induction of benign tumors. These viruses are divided into high-risk types (e.g., high-risk HPV type 16 [HR-HPV-16] and -18), which have the capability of inducing anogenital malignancies, and low-risk types (e.g., LR-HPV-6 and -11), which induce hyperproliferative mucosal lesions and are rarely associated with malignancy. Mucosal HPV infections tend to clear on their own, but in some cases, latent infection could be established and may persist for years. Cutaneous ␤-genus HPV infections are highly prevalent in the general population and tend to persist (14). Vaccines based on virus-like particles made up of the capsid protein L1 have been developed against and Gardasil/Silgard [Merck Research Laboratories]). Because these virus types are responsible for only a portion of all HPV-induced malignant and benign tumors, a clear need exists for vaccines or antivirals against a broader spectrum of pathogenic HPV types.Despite the differences in viral pathogenesis, progeny virion production invariably depends on cell differentiation and occurs only in terminally differentiated keratinocytes. HPVs require the host's replication machinery to reproduce their genomes, and these viruses have developed a unique replication strategy that is adapted to keratinocyte di...

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Betapapillomaviruses: Innocent bystanders or causes of skin cancer

Cited by 90 publications

References 91 publications

Improved detection reveals active β-papillomavirus infection in skin lesions from kidney transplant recipients

Improved detection reveals active β-papillomavirus infection in skin lesions from kidney transplant recipients

Multicenter Study of the Association between Betapapillomavirus Infection and Cutaneous Squamous Cell Carcinoma

Development of a Cellular Assay System To Study the Genome Replication of High- and Low-Risk Mucosal and Cutaneous Human Papillomaviruses

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