分化型甲状腺癌的关键基因突变、分子诊断及靶向治疗研究进展

Research progress on key gene mutations, molecular diagnosis, and targeted therapy in differentiated thyroid carcinoma

摘要:

分化型甲状腺癌（DTC）总体预后良好，但其恶性进展及对放射性碘治疗的抵抗与多种驱动基因突变密切相关。BRAF、RAS、TERT、RET等关键基因不仅影响肿瘤的分化程度、侵袭行为及复发风险，也为风险分层、预后评估及个体化治疗提供重要依据。近年来，多基因检测技术的普及显著提升了细胞学不确定结节的诊断准确率，并在局部进展期病例的新辅助治疗决策中发挥关键作用。靶向治疗方面，多靶点酪氨酸激酶抑制剂以及BRAF、RET等特异性靶向药物显著改善了放射性碘难治性DTC患者的生存结局，但耐药与相关不良反应仍是限制长期获益的重要瓶颈。新近研究正在探索双靶组合和靶向联合免疫治疗，以期进一步提高疗效。本文综述DTC主要基因突变的临床意义、多基因检测的应用价值以及靶向治疗的研究进展，为精准管理提供参考。

Abstract:

Differentiated thyroid carcinoma (DTC) generally carries a favorable prognosis; however, its malignant progression and resistance to radioactive iodine therapy are strongly associated with specific driver gene mutations. Alterations in key genes-such as BRAF, RAS, TERT, and RET-not only influence tumor differentiation, aggressiveness, and recurrence risk but also provide critical molecular information for risk stratification, prognostic evaluation, and individualized therapeutic decision-making. With the increasing availability of multi-gene testing, the diagnostic accuracy for cytologically indeterminate thyroid nodules has markedly improved, and gene profiling has become essential in guiding neoadjuvant strategies for locally advanced disease. Targeted therapies, including multi-kinase inhibitors and gene-specific inhibitors (e.g., BRAF and RET inhibitors), have significantly improved survival outcomes in patients with radioactive iodine-refractory DTC. Nevertheless, acquired resistance and treatment-related adverse events remain major limitations. Emerging evidence suggests that dual-target inhibition and combinations of targeted therapy with immunotherapy may yield additional clinical benefits. This review summarizes the clinical implications of major gene mutations in DTC, the application of multi-gene testing, and recent advances in targeted therapies to support precision management.