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.

Genetic findings in treatment-naïve and proton-beam-radiated iris melanomas: Table 1

“…This result again differs from the current study, in which only a single case demonstrated polysomy 8q. Although the frequency of monosomy 3 and polysomy 8q detected in IM in our cohort is lower (15% and 6%, respectively) than that described in the two above-mentioned papers, it is consistent with that of genetic alterations commonly reported in choroidal melanomas 12 17–19. It is possible that the differing frequencies of chromosomal alterations observed in IM reflect varying genetic analytical techniques used in the studies.…”

“…In contrast, most (if not all) studies have not found BRAF mutations in either primary or metastatic posterior UM 12. Intriguingly, however, Henriquez et al 27 reported T1799A mutations in the BRAF gene in 9/19 (47%) cases of IM.…”

“…Posterior UM show distinct chromosomal alterations, which clearly correlate with the risk of metastatic death 12. Hence, ocular oncology centres are offering molecular prognostic testing using various cytogenetic techniques, such as fluorescence in situ hybridisation (FISH), comparative genomic hybridisation, spectral karyotyping, microsatellite analysis (MSA), multiplex ligation-dependent probe amplification (MLPA) and SNPs 11–14 16–23…”

Prognostic parameters in uveal melanoma and their association with BAP1 expression

“…[4][5][6] originally, loss of one chromosome 3 was identified as an important marker of poor prognosis, and this has been substantiated in many studies. However, later studies have also identified the importance of other chromosomes: gain of chromosome 8q is also correlated with death due to metastases, [5][6][7][8][9][10][11][12][13][14] while an extra chromosome 6p is associated with a better survival. 8 10 15-18 In separate studies, gene expression profiling has also been identified as a reliable method for prognostication.…”

Ocular Melanoma: Advances in Diagnostic and Therapeutic Strategies

“…However, increased apoptosis could only be found in combination with a PI3K inhibitor, leading to reduced AKT activity [50,51]. Indeed, MEK inhibitors also inhibit the proliferation of uveal melanoma cells, in a mutant GNAQ/GNA11-dependent manner.…”