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

TL;DR

This study found that gene fusions in thyroid tumors are linked to chronic lymphocytic thyroiditis and identified new gene fusions, some previously seen only in other cancers.

Contribution

The study reports novel gene fusions in thyroid cancer and links gene fusion-driven tumors to chronic lymphocytic thyroiditis.

Findings

Three gene fusions previously reported only in nonthyroid malignancies were found in thyroid carcinoma.

Florid chronic lymphocytic thyroiditis was independently associated with gene fusion–positive tumors.

Novel gene fusions produced in-frame translation products and were linked to mRNA expression.

Abstract

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.

We identified both known and novel gene fusions in thyroid neoplasia, including several previously reported only in nonthyroid malignancies. Gene fusion–positive tumors were significantly (p < 0.001, annotated as ***) associated with florid chronic lymphocytic thyroiditis, unlike tumors driven by somatic mutations or copy number variations. Our findings expand the spectrum of molecular alterations in thyroid neoplasia and suggest a potential biological link between gene fusions and chronic inflammation.

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