The biology of uveal melanoma

Abstract

Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment.

Uveal Melanoma in Ireland

“…Historically, uveal melanoma size at diagnosis was believed to be the most important clinical prognostic factor related to prognosis and survival [30, 31]. However, recent studies have clearly underscored the importance of cytogenetics (aberrations in chromosome 1, 3, 6, and 8 and mutations in BRCA1-associated protein 1, BAP1, or the splicing factor SF3B1dd) [38-42] and gene expression profile (class 2) [43-46] in determining prognosis in uveal melanoma. Additionally, other recognised clinical and histopathological negative predictive factors include ciliary body location, diffuse tumour configuration, extraocular extension, epitheloid cell type, and advanced staging [47-56].…”

Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma

“…3,4 UM prognosis is based on clinicopathologic factors, and, most importantly, on molecular and genetic markers. [5][6][7][8][9][10] UM typically exhibits recurring chromosomal abnormalities, which are related to tumor progression. 11 Recently, Yavuzyigitoglu et al 12 hypothesized that UM with specific mutations are characterized by different mechanisms causing different types of chromosomal abnormalities.…”

Recent advances in uveal melanoma treatment

“…PLCβ 4 is a downstream effector of Gαq signaling that catalyzes the formation of IP3 and DAG from PIP2. A gain‐of‐function aminoacidic substitution (Asp630Tyr) has been observed in a highly conserved catalytic core of PLCβ4 leading to a permanent activation of the GNAQ signaling pathway . Thus, even in GNAQ/11 wild‐type UM, the activation of GNAQ/11 signaling seems to play a critical role in UM development.…”

“…Chromosome 8q gain occurs in almost 40% of UM and is also associated with metastasis. This arm of chromosome 8 harbors several potential oncogenes including the V‐Myc Avian Myelocytomatosis Viral Oncogene Homolog ( MYC ), the Development And Differentiation‐Enhancing Factor 1 ( DDEF1/ASAP1 ), and the Nijmegen Breakage Syndrome 1 ( NSB1/NBN ) . The gain of this chromosome results in an overexpression of these oncogenes.…”

“…It is the most common primary intraocular malignancy in adults with an incidence of five annual cases per million in the United States . Approximately 50% of patients with UM develop metastases and succumb to the disease . Due to the unique vasculature of the eye and the distinct biology of the tumor, the predilection site for the metastatic spread is the liver.…”