Cancer is a common cause of morbidity and mortality in domestic cats. Because the mutational landscape of domestic cat tumors remains uncharacterized, we performed targeted sequencing of 493 feline tumor–normal tissue pairs from 13 tumor types, focusing on the feline orthologs of ~1000 human cancer genes. TP53 was the most frequently mutated gene, and the most recurrent copy number alterations were loss of PTEN or FAS or gain of MYC . By identifying 31 driver genes, mutational signatures, viral sequences, and tumor-predisposing germline variants, our study provides insight into the domestic cat oncogenome. We demonstrate key similarities with the human oncogenome, confirming the cat as a valuable model for comparative studies, and identify potentially actionable mutations, aligning with a “One Medicine” approach.

Pleuropulmonary blastoma (PPB) is a rare, paediatric, mesenchymal, pulmonary neoplasm that can be highly aggressive. To date, there are only two reports of PPB in animals. We describe the finding of pulmonary neoplasms with PPB-like features in two unrelated Labrador Retrievers. Both dogs presented with acute dyspnoea, pneumothorax and pulmonary lesions. Treatment consisted of emergency thoracostomy tube placement followed by lung lobectomy. At follow-up, one dog experienced no recurrence 20 months post-surgery, whereas recurrence developed in the second dog 2 years postoperatively. Histopathological examination revealed spindle-shaped neoplastic cells with blastematous-to-sarcomatous appearance, associated with cystic spaces lined by non-neoplastic respiratory epithelium. Immunohistochemistry showed that the neoplastic cells were positive for mesenchymal markers but negative for epithelial and neuroendocrine markers, with some tumour cells showing desmin positivity, supportive of myogenic differentiation, possibly compatible with rhabdomyoblastic differentiation. Genome profiling revealed a heterogeneous somatic landscape. No pathogenic somatic or germline DICER1 variants were found. We compared these findings with those reported in human PPB. This is the first comprehensive analysis of pulmonary neoplasms with PPB-like features in animals, and reveals parallels with PPB in humans, further supporting the ‘One Medicine’ approach.