Molecular pathology of uveal melanoma

Abstract

Like other cancers, uveal melanomas (UM) are characterised by an uncontrolled, clonal, cellular proliferation, occurring as a result of numerous genetic, and epigenetic aberrations. Signalling pathways known to be disrupted in UM include: (1) the retinoblastoma pathway, probably as a result of cyclin D1 overexpression; p53 signalling, possibly as a consequence of MDM2 overexpression; and the P13K/AKT and mitogen-activated protein kinase/extracellular signal-related kinase pathway pathways that are disturbed as a result of PTEN and GNAQ/11 mutations, respectively. Characteristic chromosomal abnormalities are common and include 6p gain, associated with a good prognosis, as well as 1p loss, 3 loss, and 8q gain, which correlate with high mortality. These are identified by techniques such as fluorescence in situ hybridisation, comparative genomic hybridisation, microsatellite analysis, multiplex ligationdependent probe amplification, and singlenucleotide polymorphisms. UM can also be categorised by their gene expression profiles as class 1 or class 2, the latter correlating with poor survival, as do BRCA1-associated protein-1 (BAP1) inactivating mutations. Genetic testing of UM has enhanced prognostication, especially when results are integrated with histological and clinical data. The identification of abnormal signalling pathways, genes and proteins in UM opens the way for target-based therapies, improving prospects for conserving vision and prolonging life.

HOXA11 antisense long noncoding RNA (HOXA11‐AS): A promising lncRNA in human cancers

“…Uvea is the second most common site for melanoma following the skin, and Uveal melanoma (UM) is known as the most common type of primary intraocular tumor in adults. UM possesses high metastatic ability that may cause up to 50% patients liver metastasis 14. In‐depth understanding of the melanomagenesis, both epigenetic and genetic, may assist in the prevention, diagnosis, and intervention for UM.…”

Expression of focal adhesion kinase in uveal melanoma and the effects of Hsp90 inhibition by 17-AAG

“…It is reasonable to speculate that the overexpression of FAK plays a role in UM through aberrant interactions in FAK-mediated transduction pathways. For example, the MAPK and PI3K-AKT signaling pathways are constitutively activated through multiple mechanisms in UM [12], and FAK has been implicated as a signaling mediator required for the activation of these pathways [14]. FAK is also involved in many pertinent cellular processes such as secretion of matrix-metalloproteinases and matrix remodeling, epithelial mesenchymal transition, promotion of tumor cell survival, angiogenesis, invasion, migration and anoikis [2].…”

“…Once metastatic disease has been clinically detected, available therapeutic options do not improve prognosis and the median survival rate is 9-12 months [11]. Recent progress made in the molecular approach to diagnosis has led to the identification of several therapeutic targets implicated in the metastatic cascade for UM [12]. These targets include c-Met, the receptor for hepatocyte growth factor/scatter factor (HGF/SF), the insulin-like growth factor 1 receptor (IGF-1R), and CXCR4/CXCL12 chemokine axis [13].…”

<b><i>Drosophila</i></b> as a Potential Model for Ocular Tumors

“…Whereas retinoblastoma is largely considered to be a single-gene disease, in uveal melanoma, several genetic and epigenetic lesions have been variously associated with tumor development or progression [26]. As illustrated above, multigenic models of tumorigenesis can be readily generated in the fly.…”

“…This is particularly interesting given the well-established role of certain Polycomb Group (PcG) genes as tumor suppressors in the Drosophila eye, including Sex combs extra (Sce, an E3 ligase required for H2A monoubiquitylation), which operates synergistically with the PR-DUB complex to transcriptionally repress a subset of PcG target genes [32,33]. Armed with the knowledge of some of the genetic events driving uveal melanoma [26] and given the conservation of the affected genes in flies, it will be possible to begin to devise Drosophila models with which to help determine the key players in uveal melanoma development and progression.…”