Abstract
Purpose :
In uveal melanoma (UM), heavy tumour pigmentation has been associated with a bad prognosis. Microphthalmia-associated transcription factor (MITF) is located on chromosome 3 and it is the master regulator of melanin synthesis and melanocyte development. In cutaneous melanoma, the role of MITF is not completely clear but loss of MITF is associated with epithelial-to-mesenchymal transition (EMT), an increase in stem cell markers and inflammation. In UM, MITF loss is associated with loss of expression of BAP1, which is a negative prognostic marker. We explored the role of MITF in two cohorts of enucleated UM patients: a cohort of 64 UM patients enucleated at the Leiden University Medical Centre (LUMC) and the The Cancer Genome Atlas (TCGA) cohort (n = 80).
Methods :
We analysed the relation between MITF expression in UM and clinical-pathological and genetic features and carried out survival analyses on both cohorts. Next, we tested whether MITF expression was related to pigmentation, inflammation and EMT markers in both cohorts and performed a differential expression and gene set enrichment analysis (GSEA) between MITF-low and MITF-high UM in the LUMC cohort.
Results :
In the LUMC cohort, MITF expression was lower in dark UM than in light tumours (p = 0.004). Moreover, MITF expression was lower in UM with monosomy 3 (p < 0.001) and in UM with a high expression of PRAME (p = 0.01). However, MITF expression was not significantly related to survival (p = 0.22). These results were confirmed in the TCGA cohort. In differential expression analysis, MITF-low UM showed upregulation of the inhibitory receptor TIM-3 and of several genes (such as CXCL16 and HCP5) that have been shown to increase cell proliferation and migration in other cancer types, and in GSEA, MITF-low tumours showed an upregulation of hallmark pathways involved in inflammation.
Conclusions :
Since monosomy 3, PRAME expression and inflammation are features of poor prognosis in UM, we propose that MITF loss in UM is related to tumour progression and may have a direct link with the inflammatory state. Further studies are needed to understand if the role of MITF is independent of its relation with chromosome 3 and BAP1 status.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.