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Clinical Updates

Marie-Therese Leccia, MD, PhD

UVA Carcinogenesis

Marie-Therese Leccia

Monday, September 03, 2007

Solar ultraviolet (UV) radiation is the most important environmental factor involved in the pathogenesis of skin cancers. Both UVB (290-320 nm) and UVA (320-400 nm) radiations participate in cutaneous carcinogenesis. However, the exact role of UVB, UVA, or interactions between these wavebands (and also visible and infrared radiations) remains unknown.

Epidemiological and clinical data, in addition to causing specific UV mutations in skin cancers, clearly demonstrate the role of UV irradiations in the development of skin carcinomas. Pyrimidine dimer-induced C:G to T:A and CC:GG to TT:AA mutations are considered as UV-signature mutations present in squamous and basal-cell carcinomas and induced by both UVB and UVA radiations.1

The exact role of UVB and UVA in melanoma pathogenesis is largely unknown. Using a hybrid fish model, it has been suggested that UVA may be the main factor of UV-induced melanoma.2 UVB radiation is directly absorbed by DNA and is the most energetic and mutagenic component of the solar spectrum. In contrast to UVB radiation, UVA is poorly absorbed by DNA and its genotoxic effects have been mainly linked to the induction of oxidative stress and, consequently, oxidative damages of cell components. Different studies show the mutagenic effects of UVA irradiations in cultured cells.3 Moreover, UVA induces skin tumors in mice4 and is involved in immunosuppression.5

Thus, until recently, the role of UVA in skin carcinogenesis and other cutaneous pathologies (as photodermatoses or photoaging) has been associated with reactive oxygen species (ROS). The 8-oxo-7,8-dihydro-2,-deoxyguanosine (8-oxodGuo) represents the most important DNA photooxidative lesion induced by UVA (in much larger amounts than strand breaks). However, 8-oxodGuo does not appear to be correlated with the UVA mutation spectrum, suggesting that other lesions are involved in UVA mutagenesis.

Other studies show that UVA could induce cyclobutane pyrimidine dimers (CPDs) in mammalian cells and skin, and even that the yield of CPDs could be higher than 8-oxodGuo. But in contrast to UVB, UVA only seemed to induce CPDs at TT sites without any formation of pyrimidine (6-4) pyrimidone photoproducts, suggesting that the effects of UVA could imply other mechanisms than a direct excitation pathway.

Two recent studies show the role of UVA effects on human skin. The first, by Agar et al., was done to identify whether UVA or UVB caused particular gene mutations.6 These authors used laser capture microdissection and automated sequencing of the p53 gene to identify mutations caused by UVA or UVB in potentially human pre-malignant (solar keratosis, SK) and malignant skin tumors (squamous cell carcinomas, SCC). The number of mutations caused by UVB and UVA was similar in SCC and not substantially higher than in benign SK. UVA-induced mutations were predominantly related to oxidative lesions and few CPDs and C-T transitions were found. Interestingly, there was a 77% increase in the number of ROS-induced mutations in SCC compared to SK, suggesting that reactive oxygen may drive progression of SK to SCC through increased mutations. Moreover, UVA-induced mutations were more prevalent in the lower areas of tumors, whereas UVB-induced mutations were largely limited in the upper layers of tumors. This could be linked to the fact that UVA wavelengths penetrate deeper in skin than shorter UVB wavelengths. These data, showing a predominant role of ROS in UV-induced mutations and the presence of UVA-induced mutations at a greater depth than UVB, confirm the importance of UVA radiation in skin carcinogenesis.

The second study, by Mouret et al., determined the yield of formation of different DNA lesions using the HPLC (high-performance liquid chromatography) analytical method associated with tandem mass spectrophotometry detection (for bipyrimidine photoproducts) or electrochemical detection for 8-oxodGuo, within whole human skin (from breast plastic surgery) exposed to UVA radiation.7 UVA radiation of whole skin induced CPDs mainly at TT sites in larger amounts than 8-oxodGuo (9-fold higher frequency). Moreover, TT lesions remained present 48 hours after the end of irradiations and were significantly higher for UVA (72% at 48 hours) compared to UVB (55% at 48 hours). These data of low repair rates are in agreement with previous studies. The authors also determined the protection provided by the skin against formation of DNA lesions by either UVB or UVA. Although proportions of the different photoproducts were similar in vivo and in culture for both UVB and UVA, a major difference was observed concerning the yields of formation in human skin. Indeed, UVB induced 22-fold more bipyrimidine photoproducts in keratinocyte cultures than in whole human skin, whereas UVA induced 1.5-fold lower CPDs in skin compared to cultured keratinocytes.

Thus, these authors demonstrated that UVA irradiation induced larger amount of CPDs compared to oxidative DNA lesions, mainly at TT sites, and that the multilayered structure of the skin afforded a weak protection against UVA. The persistence of CPDs in UVA-irradiated skin could reflect cell-cycle alteration or DNA repair system degradation induced by UVA-oxidative stress.


CPDs, unlike oxidative DNA lesions such as 8-oxodGuo, are probably major promutagenic DNA photoproducts for UVA radiation. The authors suggest that CPD formation under UVA could be the result of photosensitization rather than direct absorption of UVA energy. Together, these data confirm the importance of UVA radiation in skin photobiology and especially in skin carcinogenesis. As UVA radiations constitute about 95% of the natural sunlight exposure, it is of first importance to understand the carcinogenic effects of UVA and to develop adequate high UVA protective sunscreens.


  1. Kappes UP, Luo D, Potter M, et al. Short- and long-wave UV light (UVB and UVA) induce similar mutations in human skin cells. J Invest Dermatol 2006;126(3):667-75.
  2. Setlow RB, Grist E, Thompson K, et al. Wavelengths effective in induction of malignant melanoma. Proc Natl Acad Sci U S A  1993;90(14):6666-70.
  3. Stary A, Robert C, Sarasin A. Deleterious effects of ultraviolet A radiation in human cells. Mutat Res 1997;383(1):1-8.
  4. de Laat A, van der Leun JC, de Gruijl FR. Carcinogenesis induced by UVA (365 nm) radiation: the dose-time dependence of tumor formation in hairless mice. Carcinogenesis 1997;18(5):1013-20.
  5. Halliday GM. Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis. Mutat Res 2005;571(1-2):107-20.
  6. Agar NS, Halliday GM, Barnetson RS, et al. The basal layer in human squamous tumours harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis. Proc Natl Acad Sci U S A 2004;101(14):4954-9.
  7. Mouret S, Baudouin C, Charveron M, et al. Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation. Proc Natl Acad Sci U S A 2006;103(37):13765-70.