Comprehensive analysis of β‐ and γ‐human papillomaviruses in actinic keratosis and apparently healthy skin of elderly patients

Background: Vulvar squamous cell carcinoma (VSCC) is a rare malignancy of the female genital tract. We aimed to determine the mucosal high-risk human papillomavirus (HPV)-attributable fraction of VSCCs from Italian women using multiple markers of viral infections. Methods: VSCCs and 8 metastatic lymph node samples from 107 Italian women were analyzed by a highly typespecific multiplex genotyping assay for the presence of DNA from 119 different HPVs. Tissues were further analyzed for HPV RNA and for upregulation of the cellular protein p16 INK4a . Results: The rate of mucosal HPV-related tumors defined by viral DNA and RNA positivity was low (7.8%). HPV16 was the most prevalent, followed by 53, 56, and 58. Only five (4.9%) p16 INK4a -positive tumors were also positive for both viral DNA and RNA. One (14.3%) metastatic lymph node sample was positive for all three markers. DNA of cutaneous HPVs was detected in only two VSCCs, i.e. genus beta types 5 and 110. Conclusion: A small proportion of Italian VSCCs is putatively HPV-related, i.e. positive for both viral DNA and RNA of the same type, thus reinforcing the importance of HPV vaccination. Moreover, this study suggests that a direct role of HPV from genus beta and gamma in vulvar carcinogenesis is unlikely.

Section: Hpv Dna Detection and Genotypingmentioning

confidence: 99%

Role of human papillomavirus infection in the etiology of vulvar cancer in Italian women

Preti¹,

Rotondo²,

Holzinger³

et al. 2020

“…In a previous work conducted on the same population as the present study, cutaneous HPVs with oncogenic capacity (e.g., HPV5, HPV8, HPV38) were detected in more than 50% of the AK scrapings [ 22 ]. Given the high prevalence of MCPyV and HPyV6 observed here, co-infections with cutaneous HPVs are frequent.…”

Section: Discussionmentioning

confidence: 90%

“…This may have caused an underestimation of PyV prevalence in AK biopsies. Conversely, the results obtained on skin scrapings are reliable, since these specimens were fresh-frozen at − 80 °C to ensure nucleic acid preservation and have been proven to be excellent for other molecular analyses [ 22 , 45 ], thus representing a strength of the study. The very large sample size of AK represents an additional strength.…”

Section: Discussionmentioning

confidence: 99%

“…Two study groups were included: (1) patients with a clinical diagnosis of AK and a single lesion eligible for laser surgery, enrolled at the National Institute for Health, Migration and Poverty (NIHMP), Rome, Italy [ 22 ]; (2) patients with a histologically-confirmed diagnosis of AK performed at the San Gallicano Dermatological Institute (ISG), Rome, Italy. The socio-demographic data and lesion site were recorded.…”

Section: Methodsmentioning

confidence: 99%

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Prevalence of 13 polyomaviruses in actinic keratosis and matched healthy skin samples of immunocompetent individuals

Donà

Gheit

Chiantore

et al. 2022

Background Actinic keratosis (AK) is a precursor of cutaneous squamous cell carcinoma (cSCC). UV radiation is the major risk factor for AK, but certain human papillomaviruses (HPVs) of the beta genus are also involved in its development. Differently, the role of polyomaviruses (PyVs) in skin carcinogenesis is still debated. Fiftheen PyVs have been isolated from human tissues so far, including Merkel cell polyomavirus (MCPyV), the aetiological agent of Merkel cell carcinoma. Methods The presence of 13 PyVs was assessed in skin samples from AK patients (n = 342). Matched fresh-frozen scrapings from healthy skin (HS) and AK lesions from 242 patients, and formalin-fixed paraffin-embedded AK biopsies from a different cohort of 100 patients were analyzed by multiplex PyVs genotyping assay. Results The most frequent lesion site was the scalp in men (27.3%), and the cheek area in women (29.0%). Differences between men and women were significant for the scalp, the cheek area and the lips. Almost all the scrapings were PyV-positive (HS: 89.7%, AK: 94.6%; p = 0.04). The three most frequent PyVs were MCPyV, HPyV6 and JCPyV (HS: 87.2%, 58.7%, 6.6%, respectively; AK: 88.8%, 51.2%, 9.9%, respectively). HPyV9, TSPyV, BKPyV, HPyV7, LIPyV and SV40 were detected in < 2% of the scrapings. In most cases, matched HS and AK scrapings were both positive (MCPyV: 78.1%, HPyV6: 41.7%), or both negative for the individual genotypes (for the remaining PyVs). PyV prevalence in AK biopsies was 22.0%. Only MCPyV (21.0%) and HPyV6 (3.0%) were detected in these samples. Conclusions PyV prevalence in HS and AK scrapings was high, but detection of PyVs exclusively in AK scrapings was rare. PyV positivity rate in AK biopsies was modest. Further research is need to reach firm conclusions regarding the role of these viruses in AK development.

“…On the other hand, the role of cutaneous β-HPVs genus in the carcinogenesis of human skin keratinocytes is not yet fully understood. β-HPVs are abundantly present in healthy skin as well as in skin tumors such as actinic keratosis and keratoacanthoma, indicating that some HPV genotypes can be involved in the development of cutaneous carcinomas in cooperation with UV radiation [ 6 , 31 , 32 ]. Recent studies found that β-HPVs, and in particular β3, which includes HPV49, HPV75, HPV76 and HPV115, can also infect other anatomical areas besides the skin, such as the epithelium of the oral mucosa, eyebrow hair and external genitalia [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

The E6 and E7 proteins of beta3 human papillomavirus 49 can deregulate both cellular and extracellular vesicles-carried microRNAs

Chiantore

Iuliano

Mongiovì

et al. 2022

Background The β3 human papillomavirus (HPV)49 induces immortalization of primary keratinocytes through the action of E6 and E7 oncoproteins with an efficiency similar to alpha high risk (HR)-HPV16. Since HR-HPV oncoproteins are known to alter microRNA (miRNA) expression and extracellular vesicle (EV) production, we investigated the impact of HPV49 E6 and E7 proteins on miRNA profile and EV expression, and their involvement in the control of cell proliferation. Methods The miRNA expression was evaluated by a miRNA array and validated by RT-qPCR in primary human keratinocytes immortalized by β3 HPV49 (K49) or α9 HR-HPV16 (K16), and in EVs from K49 and K16. The modulation of miRNA target proteins was investigated by immunoblotting analyses. Results By comparing miRNA expression in K49 and K16 and the derived EVs, six miRNAs involved in HPV tumorigenesis were selected and validated. MiR-19a and -99a were found to be upregulated and miR-34a downregulated in both cell lines; miR-17 and -590-5p were upregulated in K49 and downmodulated in K16; miR-21 was downregulated only in K16. As for EV-carried miRNAs, the expression of miR-17, -19a, -21 and -99a was decreased and miR-34a was increased in K49 EVs. In K16 EVs, we revealed the same modulation of miR-19a, -34a, and -99a observed in producing cells, while miR-21 was upregulated. Cyclin D1, a common target of the selected miRNAs, was downmodulated in both cell lines, whereas cyclin-dependent kinase 4 was down-modulated in K49 but upregulated in K16. Conclusion These data suggest that E6 and E7 proteins of β3 HPV49 and α9 HR-HPV16 affect key factors of cell cycle control by indirect mechanisms based on miRNA modulation.