Molecular homology between human and dog on mammary and oral cancers
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Spontaneously occurring dog cancers represent excellent models of human cancers but are greatly understudied. To better utilize this valuable resource, we conducted the first comprehensive genome-wide characterization of dog mammary and oral cancers to evaluate dog-human molecular homology. For the dog mammary cancer, we performed whole genome sequencing, whole exome sequencing, RNA-seq and/or high density arrays on 12 canine mammary cancer cases, including 7 simple carcinomas and 4 complex carcinomas. Canine simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many of which faithfully recapitulate key features of human breast cancer. Canine complex carcinomas, which are characterized by proliferation of both luminal and myoepithelial cells and are rare in human breast cancer, appear to lack genomic abnormalities. Instead, these tumors have about 35 chromatin-modification genes downregulated, and are abnormally enriched with active histone modification H4-acetylation while aberrantly depleted with repressive histone modification H3K9me3. Our findings indicate the likelihood that canine simple carcinomas arise from genomic aberrations whereas complex carcinomas originate from epigenomic alterations, reinforcing their unique value. Canine complex carcinomas offer an ideal system to study myoepithelial cells, the second major cell lineage of the mammary gland. Canine simple carcinomas, which faithfully represent human breast carcinomas at the molecular level, provide indispensable models for basic and translational breast cancer research. For the dog oral cancer, we investigated 12 canine head and neck squamous cell carcinoma (HNSCC) cases, of which 9 are oral, via high density arrays and RNA-seq. The analyses reveal that these canine cancers faithfully recapitulate many key molecular features of human HNSCC. These include similar genomic copy number abnormality landscapes, analogous sequence mutation patterns, and recurrent alteration of known HNSCC genes (e.g., MYC, CDKN2A) and pathways (e.g., cell cycle, mitogenic signaling, TGFβ signaling). Amplification or overexpression of protein kinase genes, matrix metalloproteinase genes, and epithelial–mesenchymal transition genes TWIST1 and SNAI are also prominent in these canine tumors. Our study reemphasizes the value of spontaneous canine cancers in HNSCC basic research and anticancer drug discovery.