# Histopathology and Genetic Biomarkers of Choroidal Melanoma
## 5 Genetic Profile  
Mutation analysis allowed the identification of two mutually exclusive driver mutations in Guanine nucleotide-binding protein G, q polypeptide (GNAQ) (-55%) or Guanine nucleotide-binding protein G, subunit alpha-11 (_GNA11_) (-40%) in CMs. Q209 and R183 mutations of these heterotrimeric G protein alpha subunits of the Gq class can lead to the activation of multiple downstream pathways involved in proliferation and cell growth [20,21]. Unfortunately, these mutations cannot discriminate nevi from melanoma considering that they are also present in choroidal nevi [21] and neither have they been shown to be of significant prognostic value. Worse prognosis and high risk of metastasis are instead associated with the loss of chromosome 3 (monosomy of chromosome 3), in particular, when associated with polysomy 8q [22]. The gain of chromosome 6p (6p gain) is usually associated with a better prognosis, while the loss of chromosome 6q is usually found in tumors that metastasize [23]. V-Raf Murine Sarcoma Viral Oncogene Homolog B (_BRAF_) mutations, usually observed in cutaneous melanomas, are very rare in CMs [24]. _Kit_ mutations are also rare [25]. BRCA1 associated protein-1 (BAP1) is a gene located on chromosome 3 that encodes for a ubiquitin caroboxy-terminal hydrolase involved in chromatin remodeling and cell cycle control [26]. Inactivating mutations of this gene, affecting the catalytic domain of the enzyme or frameshift/non-sense mutations resulting in a non-functional protein, have been found in about 80% of metastasizing choroidal melanomas [27]. According to the literature [28], the loss of BAP1 promotes metastasis of CM because it is also involved in transendothelial migration of neoplastic  
Figure 5: Intermediate magnification showing epithelioid cell type choroidal melanoma with sparse chronic lymphocytic infiltrates (arrows) intermingled to neoplastic cells (hematoxylin and eosin; original magnification 100\(\times\)). cells. [PERSON] et al. [29] found that _BAP1_ mutation status was strongly associated with BAP1 protein immunohistochemical expression; accordingly, the absence of nuclear immunohistochemical expression of BAP1 represents an easily identifiable surrogate for the presence of BAP1 mutations. Mutations of codon 625 of Splicing Factor 3b Subunit 1 (_SF3B1_) on chromosome 2 are reported in some CMs. The encoded protein is a splice factor and is also associated with chromatin remodeling [30]. This mutation usually gives an intermediate risk of developing metastasis [31]. A translation initiation factor encoded by Eukaryotic Translation Initiation Factor 1A X-Linked (_EIF1 AX_), located at Xp22.1, is also frequently mutated in rarely metastasizing choroidal melanomas [32]. These secondary driver mutations that occur in _BAP1_, _SF3B1_, or _EIF1 AX_ are generally mutually exclusive. The risk of CM metastasis could be predicted by gene expression profiling (GEP) of 15 genes [33] (Table 1). GEP differentiates class 1 and class 2 tumors, the first class was likely to undergo metastasis, whereas the second class has a greater rate of metastasis and disease-related mortality. GEP class 1 tumors mainly contain tumors with disomy 3, the gain of chromosome 6p, and EIF1 AX or SF3B1 mutations, where monosomy 3 tumors, deletions of chromosome 8p with BAP1 mutations are mainly classified as GEP class 2 tumors. Considering cell differentiation, class 1 tumors are well-differentiated with low Ki-67 antibody positivity, class 2 tumors are composed of ectodermal stem-cell-like cells with high Ki-67 antibody positivity [34]. The Cancer Genome Atlas (TCGA) recently performed a study on 80 CMs and identified four subsets: two associated with poor-prognosis monosomy 3 and two with better prognosis disomy 3 [35]. Although advantages have been made in the knowledge of the molecular status of CM, no strongly validated therapeutical options have been introduced and the therapeutic \"landscape\" of metastatic CM, in particular, still remains largely unknown.