## 4 Discussion  
UM is an ambiguous neoplasia because regardless of the histological subtype and initial stage, it can metastasize to the liver, even after 10-15 years [4]. From the diagnosis of hepatic metastasis, death usually occurs within one year, and there is a lack of effective treatment. Asymptomatic patients with an early detection of metastasis seem to have an apparent benefit, while adjuvant therapies and screening do not seem to provide a significant survival benefit [10; 11]. The prognosis of UM depends on multiple clinical data points: adult/senile age, male gender, large tumor, tumor thickness, ciliary body site, eye or skin melanocytosis, extraocular involvement at presentation, and advanced stage. Histopathological parameters (epithelial cell variant, numerous mitoses, microvascular proliferation, microvascular loops and patterns, intratumoral lymphocytes, intratumoral macrophages, strong expression of IGF-1R (insulin-like growth factor-1 receptor) and HLA (Human Leucocyte Antigen) class I and II), cytogenetic factors (monosomy 3, chromosome 8q-gain or 8p-loss, chromosome 1p-loss, chromosome 6q-loss), and transcriptomic factors (gene expression profile class 2) [10; 11] play a role as prognostic factors. However, much remains to be understood to limit the onset of metastases or to identify effective treatments in metastatic patients. Indeed, research is being focused on factors that can identify tumors with aggressive behavior and find new therapeutic targets. Our research group has tried to determine the unusual behavior of UM by testing different molecules and factors such as ADAM10, RKIP, pRKIP, ABCB5, and SPANX-C [9; 12; 13]. Recent studies have reported the inactivation of somatic mutations in gene-encoding BRCA-1-associated protein 1 (BAP1) in about 84% of metastasing UMs [14]: the high frequency of BAP1 mutations in metastatic UMs encouraged us to search for new therapeutic strategies with the target molecule BAP1, which have deubiquitinase activity on histone H2A [15; 16]. In different tumors,  
Figure 4: Kaplan–Meier test. Survival analyses (Kaplan–Meier) in patients with UMs with low and high macroH2A expression (\(p<0.001\), log-rank (Mantel–Cox) test). including skin melanoma, mH2A and its variants, which are widely distributed along chromatin [17; 18; 19], have been regarded as a potential prognostic marker [20; 21]. Previously, [PERSON] et al. [6] reported that the histone variant mH2A suppressed the tumor progression of malignant cutaneous melanoma and that the loss of mH2A isoforms was positively correlated with increasing malignant phenotypes of cutaneous melanoma cells in culture and human tissue samples. In addition, they suggested that the tumor-promoting function of mH2A loss was mediated, at least in part, through direct transcriptional upregulation of CDK8. [PERSON] et al. [7] showed that high expression of mH2A suppressed melanoma cell progression and arrested cells in the G2/M phase. Thus, we hypothesized that an alteration in mH2A expression could contribute to a change in the phenotype of UMs, promoting tumor progression. Therefore, mH2A would be the basis for this mechanism, whose final effect would be stabilizing the cell cycle, which is frequently observed in malignant neoplasms, in particular in tumor lesions with a low proliferative index. Furthermore, the arrest of the cell cycle would make the cell not very sensitive to chemotherapy, suggesting a further predictive role in the response to therapy. In the present study, we showed that an elevated increased expression of mH2A correlated with tumor progression: indeed, metastasizing UMs showed the highest expression of mH2A. This assay might prove that a high expression of histone protein correlates with an advanced tumor phase. In this study, we saw that mH2A overexpression was a prognostic factor for the risk of metastasis. In our series of UMs, mH2A was strongly expressed in more than 75% of neoplastic cells, with a median IRS value of 12.