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.
Mucosal melanoma is a rare and poorly characterized subtype of human melanoma.,Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites.,Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53.,We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa.,A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers including MDM2, B2M, KNSTRN and BUB1B.,Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity.,Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.,Mucosal melanoma is a rare melanoma subtype that is poorly characterised.,Here, the authors sequenced human, canine, and equine melanoma samples and performed a cross-species analysis, which revealed candidate driver genes, recurrent copy number alterations in regions syntenic between species, extensive intra-tumour heterogeneity and potential germline predisposing alleles