BRAF and epithelial-mesenchymal transition in primary cutaneous melanoma: a role for Snail and E-cadherin?

Brendon Mitchell, Dominick A. Leone, John K. Feller, Shi Yang, Meera Mahalingam

In vitro studies in melanoma indicate that upregulation of the transcriptional repressor Snail occurs with a concomitant decrease of its target E-cadherin, both hallmarks of epithelial-mesenchymal transition (EMT) - an association not established in vivo. We sought to elucidate the relationship between BRAF, Snail, E-cadherin and established histopathologic prognosticators in primary cutaneous melanoma (PCM). Archived annotated samples with a diagnosis of PCM were retrieved (n=68 cases; 34 BRAF mutant and 34 BRAFWT) and immunohistochemically stained for Snail and E-cadherin protein expression. A semi-quantitative scoring system was utilized. Multivariable logistic analysis was used to control confounders of BRAF. Snail expression was significantly associated only with ulceration (42% vs. 13%, p=0.02). E-cadherin expression was present in 26% of BRAF mutant and 71% of BRAFWT cases (p=0.0003). Loss of E-cadherin expression was associated with female gender (60% vs. 34% p=0.05), BRAF mutation (74% vs. 29%, p=0.0003), thickness ≥1mm (68% vs. 32%, p=0.004), mitosis (63% vs. 25%, p=0.007), and ulceration (75% vs. 44%, p=0.05). BRAF mutation was associated with male gender (60% vs. 30%, p=0.02), Breslow thickness (p=0.007), thickness ≥1mm (68% vs. 29%, p=0.002), and ulceration (75% vs. 42% p=0.02). Snail expression did not correlate with loss of E-cadherin expression (47% vs. 53%, p=0.79). After controlling for potential confounding, BRAF mutation was associated with loss of E-cadherin (Adjusted Odds Ratio = 8.332, 95%CI: 2.257-30.757, p=0.0015) and Breslow thickness >1 mm (Adjusted Odds Ratio = 7.360, 95%CI: 1.534-35.318, p=0.0126). Our findings, indicating that mutant BRAF represses E-cadherin expression, implicate a catalytic role for BRAF in EMT.