Fusion Oncogenes in Patients With Locally Advanced or Distant Metastatic Differentiated Thyroid Cancer

Abstract Context Fusion oncogenes are involved in the underlying pathology of advanced differentiated thyroid cancer (DTC), and even the cause of radioactive iodine (RAI)-refractoriness. Objective We aimed to investigation between fusion oncogenes and clinicopathological characteristics involving a large-scale cohort of patients with advanced DTC. Methods We collected 278 tumor samples from patients with locally advanced (N1b or T4) or distant metastatic DTC. Targeted next-generation sequencing with a 26-gene ThyroLead panel was performed on these samples. Results Fusion oncogenes accounted for 29.86% of the samples (72 rearrangement during transfection (RET) fusions, 7 neurotrophic tropomyosin receptor kinase (NTRK) fusions, 4 anaplastic lymphoma kinase (ALK) fusions) and occurred more frequently in pediatric patients than in their adult counterparts (P = .003, OR 2.411, 95% CI 1.329-4.311) in our cohort. DTCs with fusion oncogenes appeared to have a more advanced American Joint Committee on Cancer (AJCC)_N and AJCC_M stage (P = .0002, OR 15.47, 95% CI 2.54-160.9, and P = .016, OR 2.35, 95% CI 1.18-4.81) than those without. DTCs with fusion oncogenes were associated with pediatric radioactive iodine (RAI) refractoriness compared with those without fusion oncogenes (P = .017, OR 4.85, 95% CI 1.29-15.19). However, in adult DTCs, those with fusion oncogenes were less likely to be associated with RAI refractoriness than those without (P = .029, OR 0.50, 95% CI 0.27-0.95), owing to a high occurrence of the TERT mutation, which was the most prominent genetic risk factor for RAI refractoriness in multivariate logistic regression analysis (P < .001, OR 7.36, 95% CI 3.14-17.27). Conclusion Fusion oncogenes were more prevalent in pediatric DTCs than in their adult counterparts and were associated with pediatric RAI refractoriness, while in adult DTCs, TERT mutation was the dominant genetic contributor to RAI refractoriness rather than fusion oncogenes.