Mast cell tumours (MCTs) are common neoplasms in dogs and are usually regarded as potentially malignant.,Several studies have attempted to identify biomarkers to better predict biological behaviours for this tumour.,The aim of this study was to identify pathways connected to clinical and histopathological malignancies, shorter survival times, and poor prognoses associated with MCTs.,We performed genome-wide gene expression analyses on tissues obtained from 15 dogs with single MCTs, and identified two distinct tumour subtypes-high-risk and low-risk-associated with differences in histological grades, survival times, Ki67 indices, and occurrence of death due the disease.,Comparative analyses of RNA sequence profiles revealed 71 genes that were differentially expressed between high- and low-risk MCTs.,In addition to these analyses, we also examined gene co-expression networks to explore the biological functions of the identified genes.,The network construction revealed 63 gene modules, of which 4 were significantly associated with the more aggressive tumour group.,Two of the gene modules positively correlated with high-risk MCTs were also associated with cell proliferation and extracellular matrix-related terms.,At the top of the extracellular matrix module category, genes with functions directly related to those of cancer-associated fibroblasts (CAFs) were identified.,Immunohistochemical analyses also revealed a greater number of CAFs in high-risk MCTs.,This study provides a method for the molecular characterisation of canine MCTs into two distinct subtypes.,Our data indicate that proliferation pathways are significantly involved in malignant tumour behaviours, which are known to be relevant for the induction and maintenance of MCTs.,Finally, animals presenting high-risk MCTs overexpress genes associated with the extracellular matrix that can be robustly linked to CAF functions.,We suggest that CAFs in the MCT stroma contribute to cancer progression.
Cutaneous mast cell tumours are one of the most common canine cancers.,Approximately 25% of the tumours metastasise.,Activating c-kit mutations are present in about 20% of tumours, but metastases occur in the absence of mutations.,Tumour metastasis is associated with significantly diminished survival in spite of adjuvant chemotherapy.,Available prognostic tests do not reliably predict whether a tumour will metastasise.,In this study we compared the global expression profiles of 20 primary cutaneous mast cell tumours that metastasised with those of 20 primary tumours that did not metastasise.,The objective was to identify genes associated with mast cell tumour metastatic progression that may represent targets for therapeutic intervention and biomarkers for prediction of tumour metastasis.,Canine Gene 1.1 ST Arrays were employed for genome-wide expression analysis of formalin-fixed, paraffin-embedded biopsies of mast cell tumours borne by dogs that either died due to confirmed mast cell tumour metastasis, or were still alive more than 1000 days post-surgery.,Decreased gene expression in the metastasising tumours appears to be associated with a loss of cell polarity, reduced cell-cell and cell-ECM adhesion, and increased cell deformability and motility.,Dysregulated gene expression may also promote extracellular matrix and base membrane degradation, suppression of cell cycle arrest and apoptosis, and angiogenesis.,Down-regulation of gene expression in the metastasising tumours may be achieved at least in part by small nucleolar RNA-derived RNA and microRNA-effected gene silencing.,Employing cross-validation, a linear discriminant analysis-based classifier featuring 19 genes that displayed two-fold differences in expression between metastasising and non-metastasising tumours was estimated to classify metastasising and non-metastasising tumours with accuracies of 90-100% and 70-100%, respectively.,The differential expression of 9 of the discriminator genes was confirmed by quantitative reverse transcription-PCR.