Clinicopathological Features of <i>CCDC6-RET</i> and <i>NCOA4-RET</i> Fusions in Thyroid Cancer: A Single-Center Retrospective Cohort Study in a Chinese Population

<b><i>Background:</i></b> The rearranged during transfection (<i>RET</i>) proto-oncogene fusion is common in papillary thyroid cancer (PTC), varying across ethnic groups. However, comprehensive comparisons of <i>RET</i> fusion types are limited. This study aims to identify predominant <i>RET</i> fusions and analyze their clinicopathological characteristics in a cohort of Chinese thyroid cancer cases. <b><i>Methods:</i></b> This single-center retrospective cohort study analyzed thyroid cancer data, utilizing next-generation sequencing on formalin-fixed, paraffin-embedded tissue samples. Detailed clinicopathological data of thyroid cancer cases with <i>RET</i> fusions were collected. <b><i>Results:</i></b> Among 2300 thyroid cancer cases, <i>RET</i> fusions were exclusively found in PTC or differentiated high-grade thyroid carcinoma (DHGTC) cases (2234 cases), absent in other types (66 cases). Of the 2234 PTC or DHGTC cases, 113 (5.06%) exhibited <i>RET</i> fusions, including 100 primary cases. Coiled-coil domain containing 6 (<i>CCDC6)-RET</i> fusions predominated (78.0%, 78/100), with nuclear receptor coactivator 4 (<i>NCOA4)-RET</i> fusions representing 22.0% (22/100). <i>NCOA4-RET</i> fusions were more prevalent in patients aged 45 years and older (54.5% vs. 28.2%, <i>p =</i> 0.021) and DHGTC cases (<i>p</i> < 0.05) and associated with higher rates of lymph node metastases (90.9% vs. 67.9%, <i>p =</i> 0.032). <i>CCDC6-RET</i> fusion exhibited a higher prevalence of Hashimoto's thyroiditis (HT) (67.9% vs. 22.7%, <i>p</i> < 0.001) and elevated thyroglobulin antibody levels (14.11 [1.86-174.32] IU/mL vs. 2.01 [1.14-15.41] IU/mL, <i>p =</i> 0.018). Moreover, <i>CCDC6-RET</i> fusion predominantly occurred in classical PTC (56.4%, 44/78) and infiltrative follicular PTC (17.9%, 14/78), whereas <i>NCOA4-RET</i> fusion was more frequent in classical PTC (36.4%, 8/22), solid PTC (27.3%, 6/22), and DHGTC (27.3%, 6/22). <i>RET</i> fusions with compound mutations were associated with older age (≥45 years) and bilateral thyroid involvement. Follow-up data showed a higher recurrence rate in the <i>RET</i> fusion group compared with the <i>BRAF^V600E</i> mutation group (5.0% vs. 0.0%, <i>p =</i> 0.018). Although the <i>NCOA4-RET</i> group showed a numerically higher recurrence rate compared with <i>CCDC6-RET</i> (9.1% vs. 3.8%), this difference was not statistically significant (<i>p =</i> 0.559). <b><i>Conclusions:</i></b> <i>RET</i> fusions are specific to PTC or DHGTC cases among Chinese thyroid cancer cases. <i>CCDC6-RET</i> and <i>NCOA4-RET</i> fusions exhibited distinct clinicopathological features, with <i>NCOA4-RET</i> being more aggressive.