Risk of Melanoma in Patients with Basal Cell Carcinoma: A Population-based Cohort Study.

Basal cell carcinoma is the most prevalent cancer in Caucasians worldwide. The aim of this study was to examine the overall risk of melanoma among patients diagnosed with basal cell carcinoma. This population-based retrospective cohort study included data from January 2010 to December 2018 from the databases of the Clalit Health Maintenance Organization and 2 major pathology laboratories in North District, Israel. The incidence and hazard ratio of melanoma in patients with a diagnosis of basal cell carcinoma were determined. Of 466,700 participants, 51% were women and the mean (standard deviation) follow-up was 6.7 (2.9; range 1-9) years. A total of 3,338 patients were diagnosed with basal cell carcinoma during the study period, 82 of whom subsequently developed melanoma. Patients with basal cell carcinoma had a significantly higher incidence of melanoma than patients without basal cell carcinoma (2.46% vs 0.37%; p < 0.0001). Univariate Cox regression analysis revealed a hazard ratio of 6.6 (95% confidence interval: 3.6-12.1; p < 0.0001) for melanoma in patients with a diagnosis of basal cell carcinoma. In conclusion, a diagnosis of basal cell carcinoma confers a significant risk of melanoma.

The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome.

An effective epidermal barrier requires structural and functional integration of adherens junctions, tight junctions, gap junctions (GJ), and desmosomes. Desmosomes govern epidermal integrity while GJs facilitate small molecule transfer across cell membranes. Some patients with severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, caused by biallelic desmoglein 1 (DSG1) mutations, exhibit skin lesions reminiscent of erythrokeratodermia variabilis, caused by mutations in connexin (Cx) genes. We, therefore, examined whether SAM syndrome-causing DSG1 mutations interfere with Cx expression and GJ function. Lesional skin biopsies from SAM syndrome patients (n = 7) revealed decreased Dsg1 and Cx43 plasma membrane localization compared with control and nonlesional skin. Cultured keratinocytes and organotypic skin equivalents depleted of Dsg1 exhibited reduced Cx43 expression, rescued upon re-introduction of wild-type Dsg1, but not Dsg1 constructs modeling SAM syndrome-causing mutations. Ectopic Dsg1 expression increased cell-cell dye transfer, which Cx43 silencing inhibited, suggesting that Dsg1 promotes GJ function through Cx43. As GJA1 gene expression was not decreased upon Dsg1 loss, we hypothesized that Cx43 reduction was due to enhanced protein degradation. Supporting this, PKC-dependent Cx43 S368 phosphorylation, which signals Cx43 turnover, increased after Dsg1 depletion, while lysosomal inhibition restored Cx43 levels. These data reveal a role for Dsg1 in regulating epidermal Cx43 turnover.