# Exploring MAPK and mTOR Pathways in Feline Thyroid Tumors

## TL;DR

This study explores molecular features of feline thyroid tumors, finding similarities to human tumors, which could help improve diagnosis and treatment for both species.

## Contribution

The study identifies a rare KRAS mutation and protein activity patterns in feline thyroid tumors, suggesting cats as potential models for human thyroid cancer.

## Key findings

- A KRAS missense mutation (p.Gln232His) was found in 13% of feline thyroid tumors.
- pAKT expression was linked to multiple tumor foci in the same thyroid lobe, indicating potential aggressiveness.
- Protein activity patterns in cats closely resemble those in human thyroid tumors, especially in atypical cases.

## Abstract

Thyroid tumors commonly occur as benign growths in both humans and cats, with malignant cases being rare. This study analyzed feline thyroid tumors to identify molecular features equivalent to those found in human tumors, focusing on key gene mutations and protein activities involved in tumor development. Although common human mutations were absent, a rare mutation was detected in some feline tumors. Protein activity patterns in cats closely resembled those seen in humans, especially in more atypical tumors. One protein’s presence was linked to multiple tumor sites in the same thyroid lobe, suggesting it may indicate tumor aggressiveness. These findings highlight the potential of cats as comparative models for human thyroid tumors, which could improve diagnosis and treatment for both species, pending further research.

Thyroid tumors are common in humans and cats, occurring most commonly as benign lesions, whereas thyroid carcinoma is barely detected in both species. Determining the mutational status of MAPK-related genes (BRAF, NRAS, HRAS, and KRAS) and the activation status of MAPK and mTOR pathways is crucial for establishing the diagnosis, treatment, and prognosis of human patients. So far, the role of such players in feline thyroid tumorigenesis remains underexplored. This study aims to elucidate the presence and implications of potential shared molecular mechanisms between human and feline thyroid tumors. Fifteen formalin-fixed paraffin-embedded feline thyroid epithelial tumors (four tumors with atypia and 11 with no atypia) were collected to perform mutational and immunohistochemical analyses. Sanger sequencing targeting human homologous hotspots revealed no mutations in BRAF (human codon 600) or RAS (human codon 61) regions. A KRAS missense mutation (p.Gln232His) was identified in two tumors with no atypia of follicular pattern (2/15, 13%). Regardless of the mutational status, pERK (Thr202/Ty204) was immuno-expressed in 10/11 (91%), pS6 (Ser235/236) in 100%, and pAKT (Ser473) in 8/11 (73%) of the tumors with no atypia. The expression patterns of pERK, pS6, and pAKT and their associations with clinical-pathological features seem to mirror the progression dynamics observed in human thyroid tumorigenesis. pAKT expression was associated with the presence of multiple tumor foci within the same thyroid lobe, suggesting its potential as a marker of aggressiveness in feline thyroid tumors. This study introduces cats as potential animal models for human thyroid tumorigenesis, with further research required to confirm such potential.