Ephrin receptors (EPH): Epha1, EPHA5, and EPHA7 expression in uveal melanoma—associations with clinical parameters and patient survival

Uveal melanoma is the most common primary intraocular malignancy in adults. The development of distant metastases is associated with a poor prognosis. Ephrine receptors (Eph) are the largest subpopulation of tyrosine kinase receptors. They play an important role in processes related to the formation and progression of cancer. The aim of the study was to evaluate the expression of ephrin receptors EphA1, EphA5, and EphA7 in uveal melanoma and its associations with clinicopathological parameters, overall survival, and disease-free survival. The study included 94 previously untreated patients who underwent enucleation due to uveal melanoma. High expression of EphA1 was positively correlated with a smaller tumor size, less frequent extra-scleral extension, lower mitotic activity, and more frequent vitreous hemorrhage. High expression of EphA5 was associated with less frequent chromosome 3 loss, absence of distant metastases, and more frequent vitreous hemorrhage. High expression of EphA7 was associated with a more frequent primary tumor location in the posterior pole. High EphA5 expression was associated with longer overall survival time. The above findings indicate that high expression of EphA1 and EphA5 can be considered a beneficial prognostic factor in uveal melanoma. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

The prognostic values of parp-1 expression in uveal melanoma

Background: Uveal melanoma is the most common primary intraocular malignancy in adults. In advanced cases, the prognosis is very poor. Thus far, no effective methods of pharma-cotherapy of this cancer have been found. The aim of the study was to evaluate the expression of PARP-1, the best-known member of the family of poly(ADP-ribose) polymerases, in uveal melanoma and its associations with clinicopathological parameters, overall survival, and disease-free survival. Methods: The study included 91 patients who underwent enucleation due to uveal melanoma. PARP-1 expression was assessed by immunohistochemistry. Results: High PARP-1 expression was associated with more frequent chromosome 3 loss, higher histopathological grade, bigger tumor size, and absence of intrascleral extension. High PARP-1 expression was associated with shorter overall survival time and disease-free survival time. Conclusions: The above findings indicate that high expression of PARP-1 can be considered as an unfavorable prognostic factor in uveal melanoma. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Histone deacetylase (Hdac)−1, −2, −4, and −6 in uveal melanomas: Associations with clinicopathological parameters and patients’ survival

Background: Uveal melanoma (UM) represents the most common primary intraocular malignancy in adults, exerting high metastatic potential and poor prognosis. Histone deacetylases (HDACs) play a key role in carcinogenesis, and HDAC inhibitors (HDACIs) are currently being explored as anti‐cancer agents in clinical settings. The aim of this study was to evaluate the clinical significance of HDAC−1, −2, −4, and −6 expression in UM. Methods: HDAC−1, −2, −4, and −6 expression was examined immunohistochemically in 75 UM tissue specimens and was correlated with tumors’ clinicopathological characteristics, the presence of tumor‐infiltrating lymphocytes (TILS), as well as with our patients’ overall survival (OS). Results: HDAC−2 was the most frequently ex-pressed isoform (66%), whereas we confirmed in addition to the expected nuclear expression the presence of cytoplasmic expression of class I HDAC isoforms, namely HDAC−1 (33%) and HDAC−2 (9.5%). HDAC−4 and −6 expression was cytoplasmic. HDAC−1 nuclear expression was associated with increased tumor size (p = 0.03), HDAC−6 with higher mitotic index (p = 0.03), and nuclear HDAC−2 with epithelioid cell morphology (p = 0.03) and presence of tumor‐infiltrating lympho-cytes (p = 0.04). The association with the remaining parameters including Monosomy 3 was not significant. Moreover, the presence as well as the nuclear expression pattern of HDAC−2 were correlated with patients’ improved OS and remained significant in multivariate survival analysis. Conclusions: These findings provide evidence for a potential role of HDACs and especially HDAC−2 in the biological mechanisms governing UM evolution and progression. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

EPHA2, EPHA4, and EPHA6 Expression in Uveal Melanomas: Searching for the Culprits of Neoplasia

Uveal melanomas (UMs) comprise the most common primary intraocular malignancies in adults, with the eye representing the second most common site for melanoma, following the skin. Prognosis remains poor, with approximately half of the cases presenting with metastatic disease at the time of diagnosis. Erythropoietin-producing human hepatocellular receptors (EPHs) comprise the largest known family of tyrosine receptors, in which, along with their ligands, ephrins, play an important role in a plethora of processes in human physiology, and are implicated in key steps of carcinogenesis. In the present study, EPHA2, EPHA4, and EPHA6 immunohistochemical expressions were investigated in UM tissues and further correlated to a multitude of clinicopathological parameters, including disease stage and patients’ overall survival (OS). High levels of EPHA2 expression were significantly associated with increased tumor vertical thickness (p = 0.03) and the presence of intrascleral involvement (p = 0.05), whereas high EPHA6 nuclear expression was associated with older age at diagnosis (p = 0.03) and absence of retinal detachment (p = 0.05). In a multivariate survival analysis, increased EPHA4 expression was associated with shortened OS along with the presence of metastasis (p < 0.001) and monosomy 3 (p = 0.02). In a separate model, the concurrent overexpression of at least two of the investigated EPHs (HR = 14.7, p = 0.03) also proved to be an independent poor prognostic factor. In conclusion, our results implicate these specific members of the EPHA group as potential biomarkers for disease prognosis as well as possible targets for the development of novel therapeutic interventions. © 2022 by the authors. Licensee MDPI, Basel, Switzerland