ABSTRACT
BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular tumour in dogs. There is no effective means of predicting whether a tumour will metastasize. microRNA (miRNA) metastasis signatures have been identified for several human cancers, including UM. AIMS: In this study we investigated whether metastasizing and non-metastasizing canine UMs can be distinguished by miRNA expression levels. MATERIALS AND METHODS: miRNA microarray profiling was used to compare miRNA expression in 8 metastasizing and 12 non-metastasizing formalin-fixed, paraffin-embedded (FFPE) primary UM biopsies. RESULTS: Fourteen miRNAs exhibited statistically significant differences in expression between the metastasizing and non-metastasizing tumours. Class prediction analysis pinpointed 9 miRNAs which categorized tumours as metastasizing or non-metastasizing with an accuracy of 89%. Of the discriminating miRNAs, 8 were up-regulated in metastasizing UM, and included 3 miRNAs implicated as potential "metastasis activators" in human cutaneous melanoma. The expression of 4 of the miRNAs was subsequently measured using the quantitative reverse transcription polymerase chain reaction (RT-qPCR), and their up-regulation in metastasizing tumours validated. CONCLUSION: miRNA expression profiles may potentially be used to identify UMs that will metastasize, and miRNAs that are up-regulated in metastasizing tumours may be targets for therapeutic intervention.
Subject(s)
Dog Diseases/metabolism , Melanoma/veterinary , MicroRNAs/metabolism , Uveal Neoplasms/veterinary , Animals , Dog Diseases/pathology , Dogs , Female , Male , Melanoma/metabolism , Melanoma/pathology , Oligonucleotide Array Sequence Analysis/veterinary , Reverse Transcriptase Polymerase Chain Reaction/veterinary , Uveal Neoplasms/metabolism , Uveal Neoplasms/pathologyABSTRACT
OBJECTIVE: To evaluate if 14 genes that discriminate metastasising and non-metastasising human uveal melanomas can differentiate metastasising and non-metastasising uveal melanomas in dogs. METHODS: Nineteen archival biopsies of eyes with a histopathological classification of primary benign (n = 9) and malignant (n = 10) uveal melanoma were selected. Thoracic and/or abdominal metastases confirmed metastatic spread of the primary tumour in seven dogs during the follow-up period. Gene expression was assayed by Reverse Transcription-quantitative Polymerase Chain Reaction. Genes displaying statistically significant differences in expression between the metastasising and non-metastasising tumours were identified. RESULTS: Four genes (HTR2B, FXR1, LTA4H and CDH1) demonstrated increased expression in the metastasising uveal melanomas. CLINICAL SIGNIFICANCE: This preliminary study illustrates the potential utility of gene expression markers for predicting canine uveal melanoma metastasis. The genes displaying elevated expression in the metastasising tumours are part of a 12-discriminating gene set used in a routine assay, performed on fine needle aspirate biopsies collected without enucleation, for predicting human uveal melanoma metastasis. Further work is required to validate the results.
