Loss‐of‐function mutations in filaggrin gene and malignant melanoma

Abstract

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). 1 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. 2 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. 3 However, in the present casecontrol 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. 3 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. 4 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., 5 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. References1 Thyssen JP, Kezic S. Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 2014; 134: 792-799. 2 Thyssen JP, Andersen YMF, Balslev E et al. Loss-of-function mutations in filaggrin gene and malignant melanoma: a case-control study. J Eur Acad Dermatol Venereol 2018; 32: 242-244. 3 Skaaby T, Husemoen LLN, Thyssen JP et al. Filaggrin loss-of-function mutations and incident cancer: a population-based study. Br J Dermatol 2014; 171: 1407-1414. 4 Gilchrest BA, Eller MS, Geller AC, Yaar M. The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med 1999; 340: 1341-1348. 5 Sch€ afer I, Mohr P, Zander N, F€ olster-Holst R, Augustin M. A...

Rare variant contribution to human disease in 281,104 UK Biobank exomes

“…For example, 12.1% of the European cohort carried at least one of the 373 distinct filaggrin ( FLG ) PTVs identified. These individuals had a significantly higher risk of well-known associations, including dermatitis ( P = 5.1 × 10 −95 ; OR: 1.96 (95% CI: 1.84–2.08)) and asthma ( P = 3.1 × 10 −32 ; OR: 1.24 (95% CI: 1.19–1.28)) 36 , but were also at risk of under-recognized associations, such as melanoma ( P = 4.7 × 10 −13 ; OR: 1.21 (95% CI: 1.15–1.27)) 37 and basal cell carcinoma ( P = 9.9 × 10 −10 ; OR: 1.19 (95% CI: 1.12–1.25)) 38 . Concomitant increases in the levels of vitamin D ( P = 2.3 × 10 −131 ; β: 0.15 (95% CI: 0.14–0.16)) 39 suggest that the increased risk of skin cancer may be attributable to increased sensitivity to ultraviolet B radiation.…”

Skin Barriers in Dermal Drug Delivery: Which Barriers Have to Be Overcome and How Can We Measure Them?

“…Therefore, absence of filaggrin appears to only predispose the skin for barrier impairment whereas further damages (e.g., mechanical stress) are required to induce a relevant barrier disruption. It also has to be taken into account that filaggrin is not only involved in structural organization of the corneocytes but its degradation products urocanic acid and pyrrolidine carboxylic acid contribute to an acidic skin pH and retention of water [ 34 , 35 ], which are important for proper barrier formation (see below).…”

Bioinformatic Analysis Identifies Potential Key Genes in the Pathogenesis of Melanoma

“…Filaggrin, a highly abundant protein of the stratum corneum, draw considerable attention after the discovery of its role in the aetiology of atopic dermatitis (37). Currently, Kezic S. has reported that FLG may serve as a potential biomarker for a reduced risk of melanoma (38), however, there are limited reports about the associations between FLG and melanoma. Thus, we can speculate that FLG may also play an important role in the melanoma progression as well as EGFR.…”