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Abstract：
BACKGROUND: Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making.
METHODS: We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant\'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development.
RESULTS: A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006).
CONCLUSIONS: Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC.
METHODS: We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant\'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development.
RESULTS: A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006).
CONCLUSIONS: Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC.
摘要：
背景：肿瘤基因分型对于优化晚期分化型甲状腺癌（DTC）患者的临床管理变得至关重要；然而，其在临床实践中的实施仍未定义。我们在此报告了我们通过下一代测序方法进行分子高级DTC测试的单中心经验，为了更好地定义肿瘤基因分型的方式和时间可以帮助临床决策。
方法：我们回顾性收集了2008年至2022年在IRCSSSant'Orsola-Malpighi医院接受分子谱分析的所有晚期DTC成年患者的数据。遗传改变与放射性碘化物难治性（RAI-R）相关，RAI摄取/疾病状态，以及RAI抗性（TTRR）发展的时间。
结果：发现RAI-R发育与遗传改变之间存在显着相关性（P=0.0001）。大约48.7%的RAI-R病例对TERT/TP53突变呈阳性（作为单一事件和与其他驱动基因改变的合并，比如BRAF突变,RAS突变,或基因融合)，而绝大多数RAI敏感病例携带基因融合(41.9%)或野生型(WT;41.9%)。RAI摄取/疾病状态和到达TTRR的时间与遗传改变显著相关(P=0.0001)。特别是,以TERT/TP53突变作为单一事件或合并的DTC显示较短的中位TTRR为35.4个月（范围15.0-55.8个月），与其他分子亚组相比。在Cox多变量分析后，TERT/TP53突变作为单个事件或合并与RAI-R独立相关（风险比4.14，95％CI1.51-11.32；P=0.006）。
结论：常规检测基因改变应作为临床检查的一部分，用于识别更具侵袭性的肿瘤的子集和具有可操作基因融合的肿瘤的子集，从而确保所有晚期DTC患者的适当管理。
方法：我们回顾性收集了2008年至2022年在IRCSSSant'Orsola-Malpighi医院接受分子谱分析的所有晚期DTC成年患者的数据。遗传改变与放射性碘化物难治性（RAI-R）相关，RAI摄取/疾病状态，以及RAI抗性（TTRR）发展的时间。
结果：发现RAI-R发育与遗传改变之间存在显着相关性（P=0.0001）。大约48.7%的RAI-R病例对TERT/TP53突变呈阳性（作为单一事件和与其他驱动基因改变的合并，比如BRAF突变,RAS突变,或基因融合)，而绝大多数RAI敏感病例携带基因融合(41.9%)或野生型(WT;41.9%)。RAI摄取/疾病状态和到达TTRR的时间与遗传改变显著相关(P=0.0001)。特别是,以TERT/TP53突变作为单一事件或合并的DTC显示较短的中位TTRR为35.4个月（范围15.0-55.8个月），与其他分子亚组相比。在Cox多变量分析后，TERT/TP53突变作为单个事件或合并与RAI-R独立相关（风险比4.14，95％CI1.51-11.32；P=0.006）。
结论：常规检测基因改变应作为临床检查的一部分，用于识别更具侵袭性的肿瘤的子集和具有可操作基因融合的肿瘤的子集，从而确保所有晚期DTC患者的适当管理。
