title: Evaluation of the mTOR pathway in ocular (uvea and conjunctiva) melanoma.
abstract: Ocular melanoma is the most common eye malignancy in adults. It usually arises in the uvea, mostly in the choroid and less frequently in the conjunctiva. There is no curative therapy available when it becomes metastatic. The etiopathogenesis of uvea and conjunctiva melanomas is still poorly understood. The mammalian target of rapamycin (mTOR) pathway is involved in many biological processes and has been implicated in the development of cutaneous melanoma tumours. The mTOR pathway is an important target for anticancer drug development, and an inhibitor of this pathway has already been approved for use in humans to treat advanced renal cell carcinoma. The aim of this study was to evaluate the contribution of the mTOR pathway in uvea and conjunctiva melanomas. We analysed specific mTOR pathway effectors using immunohistochemical analysis of 30 uvea and eight conjunctiva melanoma samples. We assessed the association with prognostic clinical-pathological features, and performed mutational analysis on the BRAF and NRAS genes. None of the cases had mutations in either BRAF or NRAS. Expression of phospho-AKT Thr308 was associated with metastatic uvea melanomas. In conjunctiva melanomas, overactivation of the mTOR pathway, as confirmed by high phospho-AKT Ser473 and Thr308, S6 and p4EBP1 Thr37/46 levels, was associated with adverse prognostic parameters (mitotic index and tumour thickness). Conjunctiva melanomas displayed high expression of phospho-mTOR effectors in contrast with uvea melanomas, in which PTEN seemed to downregulate the mTOR pathway. Characterizing the expression of PTEN, AKT and pS6 Ser235/236 might be a useful predictive tool for deciding whether to use mTOR inhibitors to treat conjunctiva melanomas.
authors.affiliation: Institute of Pathology and Molecular Immunology, University of Porto (IPATIMUP), São João, Porto, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Pópulo
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Rocha
authors.forename: Paula
authors.initials: P
authors.lastname: Silva
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lopes
mesh_terms: D004252:DNA Mutational Analysis; D005134:Eye Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D046888:Tissue Array Analysis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase