Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

Abstract

Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.

Imaging of Uveal Melanoma—Current Standard and Methods in Development

“…Tumors are dominated by epithelioid cells, spindle cells, or a combination of them [6][7][8][9]. Depending on the classification, there are seven (subdivided by Callender) or two (subdivided by the Armed Forces Institute of Pathology) types of cells in this tumor [6,10,11].…”

“…Patients with atypical and common cutaneous nevi and cutaneous freckles are also at risk of UM development [1]. Genetic risk factors include germline mutations in the MBD4, MLH1, PALB2, and BAP1 genes [9,15,24,25]. UM's sporadic association has been observed with mutations in the BRCA1, BRCA2, FLCN, MSH6, and CHEK2 genes [15].…”

“…These models allow for predicting overall survival (OS) or metastatic risk in patients with UM [9]. Apart from inherited genetic predisposition, novel prognostic biomarkers have also been established, including proteins involved in the DNA damage response (ATR and ATM), cell death regulation (Beclin-1, BNIP3, HDAC-2, and PARP-1), immune function (BTNL9, PD-1, and PD-L1), genes of the NF-κB pathway (c-Rel, p50, p53, p65, and RelB) receptors (EphA1 and EphA5), cancer stem cell markers (nestin and ABCB5), antioxidant response (PRDX3), kinase signaling (PLK-1), insulin sensitizing (adiponectin), and spermatogenesis (SPANX-C) [9]. Older age at the time of diagnosis [42] and the male gender are also associated with an unfavorable prognosis [16,43].…”

Identification of a prognostic model using cuproptosis-related genes in uveal melanoma

“…In adults, uveal melanoma (UVM) is the most common primary intraocular malignancy, occurring in approximately five people per million per year ( Lamas et al, 2021 ). Although local ocular treatment including brachytherapy, proton beam therapy, and enucleation could somewhat limit tumor growth ( Kapoor et al, 2016 ), life expectancy is limited once metastasis occurs.…”

The Expression of Connexin 37, 40, 43, 45 and Pannexin 1 in the Early Human Retina and Choroid Development and Tumorigenesis

“…Retinoblastoma as the most common intraocular cancer, appearing during childhood, arises from primitive retinal stem cells [ 7 ], while uveal melanoma, as the most common cancer in adult eyes, arises from the choroid [ 8 ]. If the uveal melanoma has more than 90% of spindle cells or epitheloid cells, it is called spindle or epitheloid cell melanoma, while if having more than 10% of spindle cells and less than 90% of epithelioid cells, it is called mixed cell melanoma [ 8 ]. During human retina and choroid development, numerous cells differentiate toward unique cell types using different gene expression patterns and membrane cells signaling in parallel [ 9 , 10 ].…”