Comparative genomic and clinicopathological analysis uncovers contrasting molecular profiles of canine and human thyroid carcinomas

Thyroid tumors represent 1-4% of cancers in both dogs and humans. Most canine tumors are follicular (FTC) or medullary carcinomas (MTC), unlike humans, where only 10-15% are FTC and 2% are MTC, with BRAF/NRAS or RET mutations, respectively. Here, we conduct histological and molecular analyses of canine thyroid tumors. Transcriptionally, elevated ERBB2 expression characterizes FTC tumors, whereas MTC tumors show upregulated RET signaling. Elevated HER2 protein-staining and larger tumor size associate with shorter progression-free survival. Recurrent mutations are rarely observed with potential driver variants in MEN1 (10%), KRAS (7%), and TSHR (3%), among others. Notably, mutations in DNA repair pathway genes are the most consistently shared across tumors, occurring in 60% of cases. Thus, the genomic profile of canine FTC differs significantly from that of humans, with limited reliance on RAS/RAF signaling for oncogenic progression. Conversely, RET signaling likely underlies tumorigenesis in both canine and human MTC.