We hypothesized that a substantial portion of the mutagenic alterations produced in the basal layer of human skin by sunlight are induced by wavelengths in the UVA range. Using laser capture microdissection we examined separately basal and suprabasal keratinocytes from human skin squamous cell carcinomas and premalignant solar keratosis for both UVA-and UVB-induced adduct formation and signature mutations. We found that UVA fingerprint mutations were detectable in human skin squamous cell carcinomas and solar keratosis, mostly in the basal germinative layer, which contrasted with a predominantly suprabasal localization of UVB fingerprint mutations in these lesions. The epidermal layer bias was confirmed by immunohistochemical analyses with a superficial localization of cyclobutane thymine dimers contrasting with the localization of 8-hydroxy-2-deoxyguanine adducts to the basal epithelial layers. If unrepaired, these adducts may lead to fixed genomic mutations. The basal location of UVA-rather than UVB-induced DNA damage suggests that longer-wavelength UVR is an important carcinogen in the stem cell compartment of the skin. Given the traditional emphasis on UVB, these results may have profound implications for future public health initiatives for skin cancer prevention. Human epidermis is a heterogeneous tissue composed of several distinct layers. Based on incident energy, UVA induces less direct damage to DNA than UVB (1) and therefore has been considered far less carcinogenic. However, there are many unresolved issues regarding the relative carcinogenicity of UVA and UVB in human skin. UVA is Ϸ20-fold more intense than UVB in sunlight and is absorbed by different chromophores. In vitro, whole mouse and human epidermis attenuate UVB photons to a greater extent than those of UVA, with Ͻ10% of incident UVB radiation, but with Ͼ20% of UVA reaching the basal germinative layers (2). Initiation of skin tumors presumably requires penetration of UV photons to the dividing basal͞ stem cell layer for acute DNA damage to become fixed as heritable genomic mutations (3), and more UVA than UVB would be expected to reach this basal layer. Hence, UVA may make a larger contribution to human skin cancer than is generally assumed.Despite estimates (4), neither the action spectra for skin cancer in humans nor the relative roles of UVA and UVB are known. UVB and UVA are both tumorigenic in mice (5). UVA rather than UVB mediates the dermal changes observed as photoaging, supporting a role for the increased penetrance of UVA. A large body of evidence now points to a role for UVA in skin carcinogenesis (6). G:C 3 A:T transitions are considered UVB-induced when occurring at tandem dipyrimidine (Py-Py) sites or pyrimidine (Py) runs (7). The most common base change when DNA nucleotide excision repair-proficient Chinese hamster ovary cells, hemizygotic at aprt, were irradiated with UVA was A:T 3 C:G transversion (8), and UVA induces more sequence alterations at A:T base pairs and less G:C 3 A:T transitions than UVB and UVC in transfected L...

UV radiation-induced immunosuppression augments cutaneous carcinogenesis. The incidence of skin cancer continues to increase despite increased use of sunscreens, which are less effective at preventing immunosuppression than sunburn. Using the Mantoux reaction as a model of skin immunity, we investigated the effects of solar-simulated (ss) UV and its component UVA and UVB wavebands and tested the ability of topical nicotinamide to protect from UV-induced immunosuppression. Healthy, Mantoux-positive volunteers were UV-irradiated on their backs, with 5% nicotinamide or vehicle applied to different sites in a randomized, double-blinded manner. Subsequent Mantoux testing at irradiated and adjacent unirradiated sites enabled measurement of UV-induced immunosuppression with and without nicotinamide. Suberythemal ssUV caused significant immunosuppression, although component UVB and UVA doses delivered independently did not. Men were immunosuppressed by ssUV doses three times lower than those required to immunosuppress women. This may be an important cause of the higher skin cancer incidence and mortality observed in men. Topical nicotinamide prevented immunosuppression, with gene chip microarrays suggesting that the mechanisms of protection may include alterations in complement, energy metabolism and apoptosis pathways. Nicotinamide is a safe and inexpensive compound that could be added to sunscreens or after-sun lotions to improve protection from immunosuppression. immunosuppression.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://network.nature.com/group/jidclub