Abstract
Simple SummaryUveal melanoma (UM) is a rare ocular malignancy that often gives rise to metastases. Tumours with an inflammatory phenotype have an especially bad prognosis. As an increased HLA expression and the presence of tumour-infiltrating lymphocytes and macrophages may be regulated by miRNAs, we set out to investigate whether any miRNAs are associated with inflammatory parameters in this malignancy. Some miRNAs were increased in UM with a high HLA expression and high T cell numbers, while others were decreased, showing two opposing patterns; however, both patterns were related to the tumour’s chromosome 3/BAP1 status. We conclude that specific miRNAs are related to the inflammatory phenotype and that these are differentially expressed between disomy 3/BAP1-positive versus monosomy 3/BAP1-negative UM.MicroRNAs are known to play a role in the regulation of inflammation. As a high HLA Class I expression is associated with a bad prognosis in UM, we set out to determine whether any miRNAs were related to a high HLA Class I expression and inflammation. We also determined whether such miRNAs were related to the UM’s genetic status. The expression of 125 miRNAs was determined in 64 primary UM from Leiden. Similarly, the mRNA expression of HLA-A, HLA-B, TAP1, BAP1, and immune cell markers was obtained. Expression levels of 24 of the 125 miRNAs correlated with expression of at least three out of four HLA Class I probes. Four miRNAs showed a positive correlation with HLA expression and infiltration with leukocytes, 20 a negative pattern. In the first group, high miRNA levels correlated with chromosome 3 loss/reduced BAP1 mRNA expression, in the second group low miRNA levels. The positive associations between miRNA-22 and miRNA-155 with HLA Class I were confirmed in the TCGA study and Rotterdam cohort, and with TAP1 in the Rotterdam data set; the negative associations between miRNA-125b2 and miRNA-211 and HLA-A, TAP1, and CD4 were confirmed in the Rotterdam set. We demonstrate two patterns: miRNAs can either be related to a high or a low HLA Class I/TAP1 expression and the presence of infiltrating lymphocytes and macrophages. However, both patterns were associated with chromosome 3/BAP1 status, which suggests a role for BAP1 loss in the regulation of HLA expression and inflammation in UM through miRNAs.
Highlights
Uveal melanoma (UM) is the most common type of primary intraocular malignancy in adults and carries a high risk of metastases
We looked at the association between miRs of the Rotterdam cohort of 26 UM and the mRNA levels of infiltrating cells: in agreement with the prior findings, miR-155 was positively correlated with CD4 (p = 0.02), while miR-211 was negatively correlated with CD4 and CD8 and miR-125b2 with CD4 and CD163 (Table S4)
Most UM carry a mutation in the GNAQ or GNA11 gene, which do not contribute to prognostication [44,45,46]
Summary
Uveal melanoma (UM) is the most common type of primary intraocular malignancy in adults and carries a high risk of metastases. Tumours with monosomy of chromosome 3 (M3), gain of 8q [1,2,3,4], a mutation in the BAP1 (BRCA1-associated protein-1) gene [5,6], or a class 2 gene expression profile [7,8,9] are more prone to develop metastases. Tumours that have these high-risk characteristics often show an inflammatory phenotype [10,11], characterized by the presence of high numbers of tumour-infiltrating lymphocytes and macrophages [12,13], and a high expression of the HLA Class I and II antigens [14,15,16].
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