New concepts in the molecular understanding of uveal melanoma

Uveal melanoma is the most common primary intraocular malignancy, and its metastases are deadly. Significant work has been done to elucidate the molecular framework that causes uveal melanoma development and metastasis. This review is intended to highlight the most recent breakthroughs in the molecular understanding of uveal melanoma.

Monosomy of chromosome 3 and class 2 gene-expression profile are well-known indicators of melanoma metastasis. However, some patients with disomy 3 and class 1 gene expression profiling (GEP) still develop metastasis. Disomy 3 tumors may be further classified based upon the presence of an SF3B1 mutation. The role of SF3B1 gene is unclear at this time but may be related to the development of late metastases among disomy 3 uveal melanoma. Class 1 GEP tumors have recently been subdivided into class 1a and class 1b, with class 1b tumors carrying a slightly higher risk of metastasis. Among patients with either class 1 or class 2 GEP, the expression of preferentially expressed antigen in melanoma (PRAME) is an independent risk factor for the development of metastasis. Mutation of GNAQ is the most commonly observed mutation in uveal melanoma, regardless of chromosome 3 status or GEP class. Inhibitors or GNAQ may be targets for therapeutic intervention in uveal melanoma. MicroRNA molecules are small noncoding RNA molecules that have been recently demonstrated to function in RNA silencing and posttranscriptional regulation of gene expression. These molecules may play a role in the development of uveal melanoma metastasis.

New findings such as the presence or absence of PRAME, mutations in the SF3B1 gene and microRNA dysregulation have added new layers to our understanding of uveal melanoma. These new concepts will enhance our ability to prognosticate tumor metastasis and may provide targets for therapeutic intervention.