Effects of Isthmus Topography on the Molecular Characteristics of <i>BRAF</i>-mutant Papillary Thyroid Cancer

<h4>Background/aim</h4>Previous studies suggest that thyroid cancers in the isthmus are associated with more aggressive behavior and unfavorable patient outcomes compared to lobar tumors. This study aimed to characterize the molecular features of isthmus thyroid cancer.<h4>Materials and methods</h4>Transcriptomic and proteomic data were retrieved from the Cancer Genome Atlas. We performed 1:2 propensity score matching based on age, sex, tumor subtype, size, extrathyroidal extension, lymph node metastasis, and stage, matching 15 papillary thyroid cancers with the <i>BRAF</i> V600E mutation located in the isthmus to 30 tumors in the unilateral lobar area.<h4>Results</h4>Despite balanced oncogenic drivers, <i>BRAF</i>-mutant isthmus tumors exhibited significantly lower BRAF-RAS scores and higher ERK output scores. Additionally, these tumors had a slightly elevated DNA methylation-based stemness index. Principal component analysis revealed distinct gene expression patterns between the two groups. Differential expression and gene set enrichment analysis indicated enrichment in extracellular matrix remodeling, cell adhesion pathways, and TGF-β signaling. Notable upregulated genes included oligoadenylate synthases, <i>TNR, HAS3</i>, and <i>LIF</i>. Hierarchical proteomic clustering highlighted increased co-expression of several oncoproteins and DNA damage response markers in isthmus tumors.<h4>Conclusion</h4><i>BRAF</i>-mutant papillary thyroid cancers in the isthmus display distinct molecular characteristics, including increased ERK signaling activity. These findings suggest that topographical location independently influences tumor biology and may account for the more aggressive clinical behavior of isthmus tumors at the molecular level.