• Zakaria Y Abd Elmageed, Robert F Moore, Koji Tsumagari, Michael M Lee, Andrew B Sholl, Paul Friedlander, Zaid Al-Qurayshi, Mohamed Hassan, Alun R Wang, Hamid A Boulares, and Emad Kandil.
• Department of Surgery, Tulane University School of Medicine, New Orleans, LA; Department of Pharmaceutical Sciences, Texas A&M Health Science Center, College Station, TX.
• J. Am. Coll. Surg. 2018 Apr 1; 226 (4): 526-537.

BackgroundApproximately half of cutaneous melanoma tissues harbor BRAFV600E mutations, resulting in a constitutive activation of the mitogen-activated protein kinase (MAPK) pathway. Nuclear-cytoplasmic transport machinery is dysregulated in neoplastic cells and alters the key regulatory proteins that can lead to tumor progression and drug resistance. The significance of nuclear localization of BRAFV600E has not been fully understood. We examined the clinical significance of intracellular localization of BRAFV600E in cutaneous melanoma.Study DesignImmunohistochemical analysis of BRAFV600E was performed on formalin-fixed, paraffin-embedded specimens of cutaneous melanoma (n = 91). Staining intensity was graded in a blinded manner. Correlations to clinical factors were analyzed by Fisher's exact test and 2-tailed t-test. Localization of BRAFV600E was determined in melanoma cells, and we investigated their resistance to BRAFV600E-specific inhibitor according to nuclear localization in both in vitro and in vivo models.ResultsWe included 91 patients, of whom 32% (29 of 91) had cytoplasmic BRAFV600E. Nuclear BRAFV600E was observed in 30% (27 of 91). Overall, BRAFV600E expression correlated with TNM stage (p = 0.011), mitotic activity (p = 0.010), and ulceration (p = 0.045). Nuclear BRAFV600E expression correlated with overall clinical stage (p < 0.001), tumor size (p < 0.001), regional lymph node (p < 0.017), depth of invasion (p = 0.005), Clark level (p < 0.001), mitotic activity (p < 0.001), ulceration (p < 0.001), and margin status (p = 0.017). On a cellular level, BRAFV600E was identified in the nucleus, and its translocation was serum dependent. Our in vitro and in vivo data revealed sequestration of BRAFV600E in the cytosol-sensitized resistant cells to vemurafenib; nuclear retention of BRAFV600E was associated with aggressiveness and drug resistance.ConclusionsNuclear localization of BRAFV600E is associated with melanoma aggressiveness. Further multi-institutional studies are warranted to confirm the clinical relevance of nuclear localization of BRAFV600E.Copyright © 2018 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

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