Oronasal mucosal melanoma is defined by two transcriptional subtypes in humans and dogs with implications for diagnosis and therapy

Abstract

Mucosal melanoma is a rare melanoma subtype associated with a poor prognosis and limited existing therapeutic interventions, in part due to a lack of actionable targets and translational animal models for pre-clinical trials. Comprehensive data on this tumour type is scarce, and existing data often overlooks the importance of the anatomical site of origin. We evaluated human and canine oronasal mucosal melanoma to determine whether the common canine disease could inform the rare human equivalent. Using a human and canine primary oronasal mucosal melanoma (OMM) cohort of treatment naive archival tissue, alongside clinicopathological data, we obtained transcriptomic immunohistochemical, and microbiome data from both species. We defined the transcriptomic landscape in both species, and linked our findings to immunohistochemical, microbiome and clinical data. Human and dog OMM stratified into two distinctive transcriptional groups which we defined using a species-independent 41-gene signature. These two subgroups are termed CTLA4- high and cMET-high, and indicate actionable targets for OMM patients. To guide clinical decision-making, we developed immunohistochemical diagnostic tools which distinguish between transcriptomic subgroups. For the first time, we find that OMM has conserved transcriptomic subtypes and biological similarity between the canine and human OMM, with significant implications for patient classification, treatment, and clinical trial design.