Abstract
This study characterizes the transcriptome and the cellular tumor microenvironment (TME) of conjunctival melanoma (CM) and identifies prognostically relevant biomarkers. 12 formalin-fixed and paraffin-embedded CM were analyzed by MACE RNA sequencing, including six cases each with good or poor clinical outcome, the latter being defined by local recurrence and/or systemic metastases. Eight healthy conjunctival specimens served as controls. The TME of CM, as determined by bioinformatic cell type enrichment analysis, was characterized by the enrichment of melanocytes, pericytes and especially various immune cell types, such as plasmacytoid dendritic cells, natural killer T cells, B cells and mast cells. Differentially expressed genes between CM and control were mainly involved in inhibition of apoptosis, proteolysis and response to growth factors. POU3F3, BIRC5 and 7 were among the top expressed genes associated with inhibition of apoptosis. 20 genes, among them CENPK, INHA, USP33, CASP3, SNORA73B, AAR2, SNRNP48 and GPN1, were identified as prognostically relevant factors reaching high classification accuracy (area under the curve: 1.0). The present study provides new insights into the TME and the transcriptional profile of CM and additionally identifies new prognostic biomarkers. These results add new diagnostic tools and may lead to new options of targeted therapy for CM.
Highlights
This study characterizes the transcriptome and the cellular tumor microenvironment (TME) of conjunctival melanoma (CM) and identifies prognostically relevant biomarkers. 12 formalin-fixed and paraffin-embedded CM were analyzed by Massive Analysis of cDNA Ends (MACE) RNA sequencing, including six cases each with good or poor clinical outcome, the latter being defined by local recurrence and/or systemic metastases
Pathologic T categories according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual[18] were pT1a in 9 (75.0%), pT1b in 1 (8.3%) and pT3b in 2 (16.6%) cases
The transcriptional analysis of rare tumors, such as CM, has so far been hampered by their low incidence, challenging a prospective analysis of fresh tissue. 3′-RNA sequencing methods, such as the Massive Analysis of cDNA Ends (MACE), allow transcriptome analysis of Formalin fixation and paraffin embedding (FFPE) s amples[20], in which RNA degradation predominantly occurs at the 5′ end[21]
Summary
This study characterizes the transcriptome and the cellular tumor microenvironment (TME) of conjunctival melanoma (CM) and identifies prognostically relevant biomarkers. 12 formalin-fixed and paraffin-embedded CM were analyzed by MACE RNA sequencing, including six cases each with good or poor clinical outcome, the latter being defined by local recurrence and/or systemic metastases. This study characterizes the transcriptome and the cellular tumor microenvironment (TME) of conjunctival melanoma (CM) and identifies prognostically relevant biomarkers. The present study provides new insights into the TME and the transcriptional profile of CM and identifies new prognostic biomarkers. These results add new diagnostic tools and may lead to new options of targeted therapy for CM. Conjunctival melanoma (CM) is a rare but potentially life-threatening tumor of the ocular surface associated with systemic metastasis within 10 years in 18–26% and a 10 year survival rate of 41–78%1. This study characterizes the cellular tumor microenvironment and provides a transcriptional profile of CM compared to healthy conjunctiva and analyzes the transcriptional differences between CM with poor and good clinical outcome (Fig. 1).
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