[Non-melanoma skin cancers and human papillomavirus]

Ultraviolet radiation (UV) is considered as a key environmental risk factor of non-melanoma skin cancer (NMSC), but other factors such as immunological status, genetic predisposition and infection by human papillomavirus (HPV) may also be involved. Although there is overwhelming epidemiological and molecular evidence that indicates a direct role for specific mucosal HPV-types in anogenital cancers, in particular cervical cancer, the pathogenic role of HPV in the development of NMSC remains speculative. The association between HPV and NMSC was first identified in patients with epidermodysplasia verruciformis (EV) and later in recipients of organ transplants. All these patients develop NMSC at sun-exposed sites. Cutaneous and mucosal HPV-DNA have been detected in about 60 to 90 p. 100 of NMSC, but also in benign epithelial lesions, and even in normal skin. However and although at a lower rate (about 40 p. 100), HPV-DNA have also been detected in normal skin, in particular in hair follicles, and in premalignant lesions and in NMSC from non-EV and immunocompetent subjects. Furthermore, no particular HPV type predominates and the viral load in NMSC seems lower than in benign epithelial lesions. Although all these findings argue against a direct involvement of HPV in NMSC, they may suggest a "hit and run" mechanism which no longer requires the viral agent but the activity of HPV oncoproteins. High risk mucosal HPV-types encode two major oncoproteins, E6 and E7, which inactivate two suppressor proteins, p53 and pRb respectively, and are sufficient for host-cell immortalization. A polymorphism resulting in either a proline or an arginine at codon 72 may also be a relevant risk factor for mucosal HPV-types-associated NMSC. By contrast, E6 of skin HPV-types fails to interact with p53, but prevents infected cells from UV-induced apoptosis leading thus to the propagation of deleterious UV-induced mutations. Immunosuppressive activities of HPV E6 and E7 proteins permit persistent HPV infection and the impairment of immunologic removal of UV-damaged cells. These results support a role for HPV infection in skin carcinogenesis as a co-factor in association with UV and immunosuppression.