ABSTRACT
Oral malignant melanoma (OMM) is the most common canine melanocytic neoplasm. Overlap between the somatic mutation profiles of canine OMM and human mucosal melanomas suggest a shared UV-independent molecular aetiology. In common with human mucosal melanomas, most canine OMM metastasise. There is no reliable means of predicting canine OMM metastasis, and systemic therapies for metastatic disease are largely palliative. Herein, we employed exon microarrays for comparative expression profiling of FFPE biopsies of 18 primary canine OMM that metastasised and 10 primary OMM that did not metastasise. Genes displaying metastasis-associated expression may be targets for anti-metastasis treatments, and biomarkers of OMM metastasis. Reduced expression of CXCL12 in the metastasising OMMs implies that the CXCR4/CXCL12 axis may be involved in OMM metastasis. Increased expression of APOBEC3A in the metastasising OMMs may indicate APOBEC3A-induced double-strand DNA breaks and pro-metastatic hypermutation. DNA double strand breakage triggers the DNA damage response network and two Fanconi anaemia DNA repair pathway members showed elevated expression in the metastasising OMMs. Cross-validation was employed to test a Linear Discriminant Analysis classifier based upon the RT-qPCR-measured expression levels of CXCL12, APOBEC3A and RPL29. Classification accuracies of 94% (metastasising OMMs) and 86% (non-metastasising OMMs) were estimated.
Subject(s)
Dog Diseases/genetics , Gene Expression Regulation, Neoplastic , Genome-Wide Association Study/methods , Melanoma/genetics , Mouth Mucosa/metabolism , Mouth Neoplasms/genetics , Animals , Chemokine CXCL12/genetics , Chemokine CXCL12/metabolism , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , DNA Breaks, Double-Stranded , DNA Repair/genetics , Dog Diseases/metabolism , Dogs , Female , Gene Expression Profiling/methods , Male , Melanoma/metabolism , Melanoma/pathology , Mouth Mucosa/pathology , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , Neoplasm Metastasis , Receptors, CXCR4/genetics , Receptors, CXCR4/metabolismABSTRACT
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.
