A molecular revolution in uveal melanoma: implications for patient care and targeted therapy

Abstract

Uveal melanoma is the most common primary intraocular malignancy and has a strong propensity for fatal metastasis. Recent advances in the molecular genetics of uveal melanoma are revolutionizing our understanding of this cancer and the care of patients. The development of a new molecular classification of uveal melanoma based on a widely available 15-gene expression profile now allows patients at high risk of metastasis to be identified early so that individualized management can be offered. The recent discovery of major driver mutations in uveal melanoma provide a rational basis for development of new targeted therapies. Taken together, these advances are transforming our understanding and management of uveal melanoma with the ultimate goal of improving patient outcomes.

Figure 1

Protein domain structure and mutation profile of key driver mutations in uveal melanoma. A. GNAQ and GNA11 encode closely related Gq alpha subunits that consist of helical and catalytic GTPase domains. GNAQ/11 mutations are mutually exclusive, occur at two amino acid residues (Q209 and R183), lead to constitutive protein activation, and chronically stimulate downstream growth-signaling pathways such as the mitogen-activated protein kinase (MAPK) pathway. B. BAP1 consists of a ubiquitin carboxyl-terminal hydrolase (“UCH”) catalytic domain, BARD binding domain, HCF1 binding motif (“H”), BRCA1 binding domain (“B”), and nuclear localization sequences (“NLS”). Reported non-truncating mutations (bars) and truncating mutations (pins) are indicated. C. SF3B1 consists of a U2AF2 interaction motif (“U”), SF3B14 interaction motif (“S”), and 17 non-redundant HEAT domains. The most common mutation in uveal melanoma occurs at R625 in HEAT domain 5 (large pin). Less common mutations are indicated (small bars). D. EIFAX1 consists of an N-terminal domain, oligonucleotide binding fold (“OB”), and C terminal tail. Mutations identified so far in uveal melanoma have been substitutions or deletions of 1–2 amino acids near the amino-terminus (bars). Abbreviations: C = carboxy terminus; N = amino terminus.

Figure 2

Cellular functions of proteins commonly mutated in uveal melanoma. Mutations in GNAQ and GNA11 disable GTPase activity (indicated by X), resulting in constitutive activation of downstream signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway. BAP1 encodes an enzyme that removes monoubiquitin moieties (“ub”) from specific substrates, including histone H2A, HCF1, and BRCA1. Interaction of BAP1 with ASXL family members is required for this enzymatic activity. These interactions affect chromatin structure and transcription. The SF3B1 protein is an integral component of both the major U2 and minor U12 spliceosomes. SF3B1 mutations in uveal melanoma alter the splicing of specific RNA transcripts. EIF1AX encodes an essential translation initiation factor required for the formation of proteins from mRNA. Mutations in EIF1AX have not been extensively studied but would be expected to alter the production of proteins that may promote tumor progression. Abbreviations: AKT = protein kinase B; DAG = diacylglycerol; ERK = extracellular signal-regulated kinases; Gα = G alpha subunit; Gαq = G alpha q subunit; GPCR = G protein coupled receptor; MAPK = mitogen-activated protein kinase; mTOR = mammalian target of rapamycin; MEK = mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; PKC = protein kinase C; PIP-2 = phosphatidylinositol biphosphate; PIP3 = phosphatidylinositol (3,4,5)-triphosphate; PLCβ = phosphoinositide-specific phospholipase C beta; RAF = rapidly accelerated fibrosarcoma oncoprotein.

Figure 3

Molecular classification and key genetic events in uveal melanoma. The gene expression profile-based molecular classification provides a context for understanding the key events in uveal melanoma progression. Mutations in GNAQ/11 are likely to be early events that cause increased proliferation, leading to a low-grade, pre-malignant melanocytic tumor with a class 1 gene expression profile. The vast majority of nevi become dormant and progress no further as a result of innate tumor suppression mechanisms. Rarely, such a tumor acquires additional mutations that allow it to progress to a uveal melanoma. If progression involves mutation of either SF3B1 or EIF1AX, the tumor retains the class 1 gene expression profile and has a low metastatic potential. On the other hand, if it acquires a mutation in BAP1 and loses the remaining copy of BAP1 through loss of chromosome 3, it acquires the class 2 gene expression profile and a high potential for metastasis. Boxes indicate targeted therapeutic compounds that are under investigation in uveal melanoma. Abbreviations: AKT = protein kinase B; HDAC, histone deacetylase; MEK = mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; mTOR = mammalian target of rapamycin; PKC = protein kinase C.