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

TL;DR

This study compares thyroid cancer in dogs and humans, revealing distinct molecular pathways and highlighting species-specific differences in tumor development.

Contribution

The study identifies ERBB2/HER2 and RET as key drivers in canine thyroid tumors, contrasting with human tumor profiles.

Findings

ERBB2 expression is elevated in canine follicular thyroid carcinomas.

RET signaling is upregulated in canine medullary thyroid carcinomas.

DNA repair pathway mutations are common across canine thyroid tumors.

Abstract

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.

Comprehensive molecular analysis of canine thyroid cancer (TC) uncovers distinct oncogenic pathways: ERBB2/HER2 activation in follicular TC, and RET signaling in medullary TC, mirroring human TC and highlighting species-specific mechanisms.

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