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.

Keywords: G-protein signaling; Immune checkpoint blockers; Molecular classification; Targeted therapy; YAP/TAZ signaling.

Fig. 1

Gene expression and mutational status in UM. Gene expression data from 79 cases of primary UM from the TCGA cohort were used for the identification of genes that are differentially expressed in cases that yielded distant metastases later on as compared to cases without progression to metastatic disease. Statistically significant gene expression differences were obtained by analysis using the bootstrapping algorithm significance analysis of microarrays as described [84]. Expression values over the mean value are indicated in red, values below the mean in blue, and values at the mean in white; the intensity of the color corresponds to the distances from the mean as indicated in the red-blue bar on top of the diagram. Differentially expressed genes were used for hierarchical clustering performed as described [84]. The dendrograms on top of the gene expression panel show the relationship of single samples and their agglomeration in clusters. The differences between the clusters are indicated by the length of the branches of the dendrograms. Above the dendrogram, the mutational status for GNAQ, GNA11, BAP1, SF3B1, and EIF1AX is indicated as well as chromosomal alterations (chromosome 3 monosomy, 6p and 8q gains) and the development of distant metastases and the status of the patients at the end of the follow-up. In all these cases, colored boxes indicate the presence and white boxes the absence of the alteration. Two main clusters are formed, one of which contains most of the cases that developed metastases. The mutation status of these cases evidences the correlation between chromosome 3 monosomy, BAP1 mutation, metastasis, and death. Note that this cohort contains an unusual case with mutations in both GNAQ and GNA11

Fig. 2

Multistep carcinogenesis of UM. The diagram shows a hypothesis on UM carcinogenesis based on the current state of knowledge of molecular alterations. UM develops from normal melanoblasts or melanocytes and is initiated in most cases by mutations in the Gα proteins, GNAQ or GNA11, or in CYSLTR2 or PLCB4, two genes acting in the same pathway. An important functional mediator of these mutations is ARF6 that is activated. The resulting melanoma can undergo further molecular alterations that influence the risk of progression to metastasis. Loss of one copy of chromosome 3, mutation of the tumor suppressor BAP1, and amplification of chr8q yield a high metastatic risk that can be attenuated by concomitant amplification of chr6p. Intermediate risk is also observed for cases with chromosome 3 disomy in the presence of SF3B1 mutations. Mutations in EIF1AX and the lack of any of these mutations are associated with a low risk of metastasis