LAUSR

Filaggrin, a highly abundant protein of the stratum corneum (SC), draw considerable attention after the discovery of its role in the aetiology of atopic dermatitis (AD). Next to its importance for the skin barrier function, filaggrin is the primary source of trans-urocanic acid (tUCA), a major SC chromophore able to absorb ultraviolet radiation (UVR). Hence, low filaggrin levels might lead to higher internal UVR dose because of reduced skin barrier function as well as decreased absorption of UVR by tUCA. Thyssen et al. hypothesized that the carriers of filaggrin gene (FLG) mutations might be more prone to develop malignant melanoma (MM), the deadliest form of skin cancer strongly linked with exposure to UVR. An earlier study showed an increased prevalence of actinic keratosis (AK) and squamous cell carcinoma (SCC) in homozygous FLG mutation carriers compared to controls. However, in the present case– control study, no association between FLG mutation and MM risk could be detected, in accordance with the results from the population-based study conducted by the same research group. Several reasons might explain these findings. The immune system plays a critical role in modulating and controlling the tumour progression in MM. One of important UVR effects is immunosuppression, and paradoxically, the same effect has also been shown for the photo product of tUCA, cis-urocanic acid (cUCA). Obviously, the effect of reduced filaggrin levels (i.e. tUCA) can work in opposing directions of magnitudes which are difficult to estimate. Another factor that should be considered when comparing AK and SCC with MM is their specific dose–effect pattern. While AK and SCC are largely dependent on the cumulative dose, intermittent high UVR exposure is more strongly linked to MM. Possibly, the high UVR dose causing sunburns might outweigh relatively modest (protecting) effect of tUCA. Another possible confounding factor not addressed in the study of Thyssen et al. (2018) is the presence of AD, which is more prevalent in the carriers of FLG mutations. In a recent cross-sectional study of Sch€afer et al., atopic diseases showed significantly protective against MM. Clearly, there are several pathways by which filaggrin may modify the risk for MM; however, the overall effect of FLG mutations is difficult to assess.