The genetics of uveal melanoma: an emerging framework for targeted therapy

Abstract

Summary Uveal melanoma is the second most common form of melanoma and the most common primary intraocular malignancy. Until recently, very little was known about the genetics of this aggressive cancer. Mutations in oncogenes and tumor suppressors that are common in other cancers are conspicuously absent in uveal melanoma. In recent years, however, uveal melanoma has begun to yield its secrets, and a fascinating picture is emerging of how it develops and progresses. Mutations in the Gq alpha subunits, encoded by GNAQ and GNA11, appear to be early or perhaps initiating events that require further mutations for malignant transformation. On the other hand, mutations in the BRCA1-associated protein-1 (BAP1) appear to occur later and demarcate a molecular brink beyond which metastasis becomes highly likely. BAP1 mutations can also occur in the germline, leading to a distinctive cancer predisposition syndrome. These mutations appear to be key events that provide the potential for targeted therapy. This article will review the genetic findings in uveal melanoma over the past two decades and suggest important areas for future work.

Molecular Pathology of Uveal Melanoma

“…It has been proposed that the genetic developmental pathway of UM bifurcates at an early stage to result in two very distinct genetic signatures: (1) disomy 3 with chromosome 6p gain and class 1 gene expression profile, and (2) monosomy 3 with class 2 molecular signature and a high metastatic propensity. 40,78,80,81 Later genetic events in UM development are suggested to be increasing aneuploidy and alterations in chromosome 8 (eg, gains in 8q and loss of 8p; see below for further details).…”

“…Upregulated expression of VEGF in UM; association with macrophage densities in UM [35][36][37] Increased expression of IGF-1 and IGF-1R in UM 32,38 Raised levels of hypoxia-inducible factor 1 alpha [39][40][41] 6. Tissue invasion and metastasis…”

“…Upregulation of E-cadherin and Wnt/beta-catenin signalling pathways 42,43 Downregulation of the helix-loop-helix inhibitor ID2 39,40 Increased expression of matrix metalloproteinases (MMPs) and downregulation of their tissue inhibitors (TIMPs) by UM [44][45][46][47] ALCAM expression 48 NOTCH pathway activation 49 Biallelic methylation of EFS 50 …”

“…Indirect evidence through the increased levels of the HIF1a and HIF2a transcription factors in UM [39][40][41] Hypoxia response of tumours acts by upregulating glucose transporters and multiple enzymes of the glycolytic pathway…”

Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma

“…More than 80% of UM have mutations in the genes GNAQ and GNA11, which encode for small GTPases [10]. These mutations are mutually exclusive, affecting 46% and 35% of UM cases respectively [11][12] [13].…”