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Alexandre P Moulin, Maya Bucher, Francois Majo, Michael J Nicolas; Activation of the MAP kinase pathway is involved in tumor progression of conjunctival melanocytic proliferations. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1284.
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The molecular events leading to the development of conjunctival melanoma have not been extensively studied. As activating mutations of BRAF and NRAS have recently been identified in a mutually exclusive way in 47% of conjunctival melanoma, we decided to evaluate the activation status of the MAP kinase pathway and PI3K/mTOR pathway in benign and malignant conjunctival melanocytic proliferations.
The phosphorylation status of MEK, ERK and S6 ribosomal protein was evaluated by immunohistochemistry in 35 conjunctival naevi and 31 conjunctival melanoma. Statistical analysis was performed with JUMP 8,0 software. Immunohistochemistry was assessed independently by three observers.
There was a concordance in 85%, 87,9% and 96,5% of the cases in the evaluation of the activation of MEK, ERK and S6 respectively. Discrepant cases were simultaneously reviewed to achieve complete agreement. There were 13 subepithelial nevi and 22 compound nevi. There were 14 females and 21 males with a mean age was 36.9 ± 3.6 yo (SEM). P-MEK was found in 20 nevi (59%). P-ERK was found 17 nevi (49 %). P-S6 was found in 11 nevi (49%). The melanoma group was composed of 17 females and 14 males with a mean age of 67.1 ± 3.38 yo (SEM). Using TNM classification, 10 tumors were belonging to the T1, 10 to the T2 and 11 to the T3 categories. P-MEK and p-ERK were both identified in 27 melanoma (87%). P-S6 was found in 29 melanoma (94%). The phosphorylation of MEK and ERK and S6 was significantly elevated in the melanoma compared to the nevi (p=0,0109; 0,0009 and p> 0,0001 respectively). There was also a significant correlation between the activation of MEK and ERK (p=0,0045).
Our results demonstrate in vivo a significant increase in the activation of the MAP kinase pathway in malignant conjunctival melanocytic proliferations. We also identified a significant increase in the phosphorylation of S6 ribosomal protein suggesting a contribution of the P13K/mTOR pathway to conjunctival melanoma development. The inhibition of these pathways might represent potential therapeutical options for the treatment of conjunctival melanoma.
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