Unpacking the genetic etiology of uveal melanoma

ABSTRACT

Introduction

Uveal melanoma (UM) is the most common primary intraocular tumor affecting adults. ~50% of patients will develop metastatic disease, mainly in the liver, for which there is currently no standard of care. The multi-faceted genetic etiology of UM informs prognosis and advises the clinical management of patients.

Areas covered

This review highlights the multifarious nature of the genetics that differentiate uveal nevi from UM, that initiate tumorigenesis and ultimately drive metastasis, and how these can be incorporated to multivariate models to predict whether and approximately when the metastatic disease will occur.

Expert opinion

Despite not being able to utilize current genomic biomarkers as therapeutically actionable targets in UM at present, advances in our understanding of this cancer, may lead to their inclusion to predict response to emerging therapies. Prognostication for individual patients is likely to progress from binary classifications of high- and low-metastatic risk, utilizing a multi-factorial approach to design molecular assays. Improvement in our comprehension of the genetic etiology of UM will bring us closer to the development of effective treatments.

KEYWORDS:

• BAP1
• EIF1AX
• chromosome
• copy number
• monosomy 3
• gene-expression profiling
• methylation
• microRNA
• mutation
• SF3B1
• uveal melanoma
• choroidal melanoma

Article highlights

• Uveal melanoma (UM) is a rare intraocular tumor whereby approximately 50% of patients develop metastatic disease for which there are no effective systemic chemotherapy or biological therapies at present.

• UM lacks a UV radiation mutational signature, and has a low mutational burden but has well-characterized somatic copy-number alterations in chromosome 1, 3, 6, and 8, unique mRNA signatures (Class 1a, 1b, and 2), in addition to mutations that initiate tumorigenesis and drive metastasis.

• Predicting disease progression is most accurate when it is multifaceted, incorporating genetic, clinical, and histopathological factors.

• Recent research exploring epigenetics, methylation, and the consequences of miRNA dysregulation in UM provide promising avenues to explore in terms of developing targeted therapeutics.

• The rapidly development of genomic testing in UM tissue samples and liquid biopsies will bring us closer to providing effective treatments, improving survivorship and quality of life for patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.