Ephrin Receptors and Ephrin Ligands in Uveal Melanoma: A Big Data Analysis Using Web Resources

Uveal melanoma (UVM) is a rare cancer that represents the second most common melanoma (after the cutaneous) and the most common primary intraocular malignancy in adults. Despite recent advances in the understanding of UVM pathogenesis, its prognosis remains unchanged, with half of patients dying because of liver metastasis. Erythropoietin-producing human hepatocellular receptors (EPHs) constitute the largest known family of tyrosine receptors, and, along with their ligands, EFNs, regulate key physiological processes and are implicated in cancer pathogenesis. In this study, we used open-access web bioinformatics platforms to explore and analyze big datasets provided by The Cancer Genome Atlas (TCGA) UVM cohort of patients. We profiled the genomic alterations present in a subset of UVM patients, highlighting a likely pathogenic deep deletion of <i>EPHA7</i>. Survival analysis showed that overexpression levels of <i>EPHA4</i>, <i>EPHA5</i>, <i>EPHA8</i>, <i>EPHB2</i>, and <i>EFNB2</i> are significantly associated with poor overall survival. Additionally, high expression levels of <i>EPHA4</i>, <i>EPHA5</i>, <i>EPHA7</i>, <i>EPHA8</i>, <i>EPHB2</i>, <i>EFNA2</i>, and <i>EFNB2</i> correlate with reduced progression-free interval and disease-free survival. Finally, we identified the EPHs (<i>EPHA2</i>, <i>EPHA4</i>, <i>EPHA8</i>, and <i>EPHB4</i>) and EFNs (<i>EFNA1</i>, <i>EFNA3</i>, <i>EFNA4</i>, and <i>EFNB2</i>) that are significantly overexpressed in the aggressive epithelioid histological subtype and revealed that the majority of EPHs/EFNs are overexpressed in metastatic disease. In conclusion, our results highlight that a subset of EPHs and EFNs may be associated with worse clinical outcomes (<i>EPHA4</i>, <i>EPHA5</i>, <i>EPHA7</i>, <i>EPHA8</i>, <i>EPHB2</i>, <i>EFNA2</i>, and <i>EFNB2</i>), and an aggressive histological subtype (<i>EPHA2</i>, <i>EPHA4</i>, <i>EPHA8</i>, <i>EPHB4</i>, <i>EFNA1</i>, <i>EFNA3</i>, <i>EFNA4</i>, and <i>EFNB2</i>). The potential correlation of these genes with clinicopathological parameters of UVM need to be evaluated and validated with bioinformatic and experimental approaches in well-characterized cohorts of UVM patients.