Human cancers challenge a pet model: the case of Canine Oral Melanoma

Human Mucosal Melanoma (hMM) is a rare aggressive neoplasm of neuroectodermal origin characterized by large chromosomal aberrations and a low burden of single-nucleotide polymorphisms (SNPs). Given the scarcity of available cases, pet dogs have been proposed as a reliable animal model. In pet dogs, Canine Oral Melanoma (COM) is the most common malignant tumor of the oral cavity, sharing clinical, histological, and genomic characteristics with hMM. However, in the last few years, together with the deepening of the genome-wide characterization of COMs, doubts raised from some authors on the reliability of the canine spontaneous model. To clarify these points, we thoroughly reviewed the recent literature and performed our analyses on both single genes and the whole genome. The goal was to overcome the considerations limited to the classic gene comparison and discover the common biologic properties that are altered in melanoma cancer cells, to reveal the complex path of events that ensures the survival and growth of the neoplastic population. The genome-wide analysis of the cohort revealed a profile of gained and lost chromosomal regions confirming most of the results available in the literature, while no consistent point mutations were detected in the target genes analyzed. COM, therefore, confirms to be a simpler neoplastic entity than hMM when considering the mutational burden, being instead a suitable model for the complex aberration profile, which activates or inhibits biological processes related to cancer survival and proliferation. Statistically significant dysregulated pathways, such as cellular proliferation, telomere maintenance, Tyrosine-, MAP-, PI3- kinases, and melanocytes homeostasis, are shared between COM and hMM. These similarities, however, are visible only when comparison is not limited to single aberrated driver genes and robust software-based analysis is performed. Furthermore, new evidence suggests that angiogenetic pathways could be of great relevance to the advancement of targeted therapies, which need further exploration in the next future. Altogether, the results of the scientific community confirm the closeness of genomic aberrations and pathways activation of COM and hMM. Further evidences could come from the developing epigenetic analyses and the in vitro and in vivo trial of new targeted therapies.