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.

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