The Occurrence of Gene Fusions in Thyroid Lesions and the Relation With Chronic Lymphocytic Thyroiditis

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Previously, we concluded that thyroid resections with multifocal, genetically distinct lesions more often showed florid chronic lymphocytic thyroiditis (CLT) than thyroids with clonally related multiple lesions. In this study, we characterized a consecutive cohort of thyroid lesions for molecular drivers and investigated the relationship between the molecular alteration type and florid CLT. Molecular diagnostic data from 414 patients (2016-2025) were retrospectively reviewed, including clinical information and histopathological evaluation. Gene fusion, somatic mutation, and chromosomal LOH/imbalance/copy-number analysis results were available for 342 cases. Eighty-eight gene rearrangements were identified across 86 patients. Most had been previously reported in thyroid neoplasia. Five well-known gene fusions revealed unusual breakpoints. Three gene fusions, previously reported only in nonthyroid malignancies (BRAF-TRIM24, SLC12A7-TERT, PVT1-MYC), were described for the first time in thyroid carcinoma. Three novel gene fusions (TRIM65-RET, FGFR2-WARS1, PPARGC1A-PPARɣ) produced in-frame translation products leading to corresponding mRNA expression. BRAF exon-skipping events were identified in treatment-naïve papillary thyroid carcinomas. Florid CLT (p = 0.002) and younger age (OR = 0.97 per year, p < 0.001) were independently associated with gene fusion-positive tumors. Sex, follicular nodular disease, and Graves' disease were not significant predictors. Our findings suggest an association between fusion-driven thyroid neoplasia and florid CLT, warranting further investigation.

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