Comment on 'does a history of eczema predict a future Basal cell carcinoma?'.

PM Elias and ML Williams FLG Mutations Could Explain Increased BCC in Eczema Comment on ‘Does a History of Eczema Predict a Future Basal Cell Carcinoma?’ Journal of Investigative Dermatology (2013) 133, 1676–1677; doi:10.1038/jid.2013.29; published online 21 February 2013 TO THE EDITOR Dyer et al. (2012) examined risk factors for basal cell carcinoma (BCC) in a relatively small cohort of veterans, who participated in the USA Veterans Affairs Topical Tretinoin Chemoprevention Trial. In addition to the usual, well- known predictors; that is, age, sun sensitivity, a history of prior BCCs, and occupational UV exposure, they found an association with a self-reported history of eczema (atopic dermatitis, AD). In their accompanying editorial, Gamba and Tang (2012) examine competing hypotheses to explain this new association. Because none of the Veterans Affairs (VA) subjects had been treated with calcineurin inhibitors or other immunosuppressives, they then speculate that either the chronic inflammation in AD or other forms of anti-inflammatory therapy for AD, such as topical glucocorticoids or UV phototherapy, could have favored the development of BCCs. Yet, the BCCs in the VA patients did not occur in previously eczematous sites, suggesting to us that some inherent difference in the structure of the epider- mis in subjects at risk for AD could explain the association of AD with an increased prevalence of BCCs. We pro- pose two alternate epidermis-based explanations, either or both of which could be operative. First, assuming that a substantial subgroup of these VA patients have Northern European ances- try, then as many as 40–50% of the subjects with a prior history of AD could bear loss-of-function FLG mutations (Irvine et al., 2011). Proteolytic degradation of FLG, followed by either enzymatic or non-enzymatic deimina- tion of its constituent amino acids, yields a mixture of polycarboxylic acids that includes trans-urocanic acid (t-UCA) (Scott et al., 1982), an important endogenous UV-B filter (Finlay-Jones and Hart, 1998). Reduction in the t-UCA content of stratum corneum (SC) might lead to greater UV-B penetration into the nucleated cell layers with an increased risk of malignant transfor- mation. On the other hand, t-UCA is photo-isomerized by UV-B to cis-UCA (c-UCA), a potent, local immunosuppres- sive molecule (Kripke, 1984; de Fine Olivarius et al., 1998). Thus, the possibi- lity that t-UCA deficiency, resulting from reduced FLG, could increase BCCs in this population through greater UV-B penetration must be weighed against the potential benefits of reduced c-UCA generation from t-UCA in a FLG- deficient, tumor environment. A second, less ambiguous epidermis- based explanation could be the thinner SC that occurs in AD (Cork et al., 2009; Voegeli et al., 2009). The thinner SC in AD could result from inherited, gain- of-function mutations in kallikrein7 (KLK7; Vasilopoulos et al., 2011); loss- of-function mutations in SPINK5, which encode the KLK inhibitor, LEKTI (Sprecher et al., 2001); and/or a FLG allele-dependent increase in the pH of the SC that accompanies the barrier abnormality, even in non-inflamed, filaggrin-deficient epidermis (Gruber et al., 2011). An increase in pH inevitably would lead to activation of KLKs (Cork et al., 2009; Voegeli et al., 2009). These alterations likely converge alone or additively to increase KLK activity and SC thinning in both lesional and non-lesional skin of AD (Elias and Schmuth, 2009). Because at least 50% of UV-B in lightly pigmented individuals is interdicted at the level of the SC (Thomson, 1955), a thinner- than-normal SC then would inevitably predispose to the development of BCCs Abbreviations: AD, atopic dermatitis; BCC, basal cell carcinoma; c-UCA, cis-urocanic acid; KLK7, kallikrein7; SC, stratum corneum; t-UCA, trans-urocanic acid; VA, Veterans Affairs Accepted article preview online 22 January 2013 1676 Journal of Investigative Dermatology (2013), Volume 133 by allowing penetration of a larger proportion of incident UV-B. The final message should be, how- ever, that AD is now generally acknowl- edged to display a prominent epidermal component, with several of its immuno- logical sequelae occurring downstream of a flawed barrier (Elias et al., 2008). Hypotheses of causation and association with other epidermal diseases, such as BCC, should not overlook the potential role of epidermal pathology in disease pathogenesis. CONFLICT OF INTEREST The authors state no conflict of interest. Peter M. Elias 1 and Mary L. Williams 2 Dermatology Service, Department of Veterans Affairs Medical Center, and Department of Dermatology, University of California, San Francisco, San Francisco, California, USA and 2 Departments of Dermatology and Pediatrics, University of California, San Francisco, San Francisco, California, USA E-mail: eliasp@derm.ucsf.edu REFERENCES Cork MJ, Danby SG, Vasilopoulos Y et al. (2009) Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 129:1892–908 de Fine Olivarius F, Wulf HC, Crosby J et al. (1998) Urocanic acid isomers and photosensitivity in healthy children. Br J Dermatol 139:605–9 Dyer RK, Weinstock MA, Cohen TS et al. (2012) Predictors of basal cell carcinoma in high-risk patients in the VATTC (VA Topical Tretinoin Chemoprevention) trial. 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