Abstract
Simple SummaryThis study pursued the proteomic analysis of primary uveal melanoma (pUM) for insights into the mechanisms of metastasis and protein biomarkers. Liquid chromatography tandem mass spectrometry quantitative proteomic technology was used to analyze 53 metastasizing and 47 non-metastasizing pUM. The determined proteome of 3935 proteins was very similar between the metastasizing and non-metastasizing pUM, but included the identification of 402 differentially expressed (DE) proteins. Bioinformatic analyses suggest significant differences in the immune response between metastasizing and non-metastasizing pUM. Immune protein profiling results were consistent with transcriptomic studies, showing the immune-suppressive nature and low abundance of immune checkpoint regulators in pUM, and suggest CDH1, HLA-DPA1, and several DE immune kinases and phosphatases as potential targets for immune therapy checkpoint blockade. Prediction modeling of the proteomic data identified 32 proteins capable of predicting metastasizing versus non-metastasizing pUM with 93% discriminatory accuracy.Uveal melanoma metastases are lethal and remain incurable. A quantitative proteomic analysis of 53 metastasizing and 47 non-metastasizing primary uveal melanoma (pUM) was pursued for insights into UM metastasis and protein biomarkers. The metastatic status of the pUM specimens was defined based on clinical data, survival histories, prognostic analyses, and liver histopathology. LC MS/MS iTRAQ technology, the Mascot search engine, and the UniProt human database were used to identify and quantify pUM proteins relative to the normal choroid excised from UM donor eyes. The determined proteomes of all 100 tumors were very similar, encompassing a total of 3935 pUM proteins. Proteins differentially expressed (DE) between metastasizing and non-metastasizing pUM (n = 402) were employed in bioinformatic analyses that predicted significant differences in the immune system between metastasizing and non-metastasizing pUM. The immune proteins (n = 778) identified in this study support the immune-suppressive nature and low abundance of immune checkpoint regulators in pUM, and suggest CDH1, HLA-DPA1, and several DE immune kinases and phosphatases as possible candidates for immune therapy checkpoint blockade. Prediction modeling identified 32 proteins capable of predicting metastasizing versus non-metastasizing pUM with 93% discriminatory accuracy, supporting the potential for protein-based prognostic methods for detecting UM metastasis.
Highlights
Uveal melanoma (UM), the most common primary malignancy of the eye in adults [1], is a relatively rare but aggressive cancer that progresses to fatal metastasis in about 50% of patients [2,3]
The specimens were derived from 53 metastasizing and 47 non-metastasizing primary uveal melanoma (pUM); donors included 53 males and 47 females, with an average age of 63 years old
The metastatic status of the pUM was established by a combination of detailed clinical data, as well as survival and prognostic analyses including gene expression, multiplex ligationdependent probe amplification, fluorescent in situ hybridization, and genome wide single nucleotide analysis
Summary
Uveal melanoma (UM), the most common primary malignancy of the eye in adults [1], is a relatively rare but aggressive cancer that progresses to fatal metastasis in about 50% of patients [2,3]. Primary UM (pUM) originates predominantly in the capillary-rich uveal tract (i.e., the iris, ciliary body, and choroid), which facilitates metastasis through hematogenous dissemination of the tumor cells. The mechanisms of UM metastasis remain poorly understood but involve multiple gene mutations and tumor dormancy [10]. Predominant gene mutations associated with UM metastasis include BAP1 [11], GNAQ, and GNA11 [12,13]. Current UM prognostic methods rely on cyto- or molecular-genetic [23,24,25] and gene expression analyses [26,27,28] of pUM biopsies [1,29,30]. An urgent need exists for improved prognostic methods [31], including an effective liquid assay for circulating pUM cells, which could facilitate earlier detection and treatments [32]
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