Thyroid Research Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, PR China.
J Clin Endocrinol Metab. 2024 Nov 18;109(12):3166-3175. doi: 10.1210/clinem/dgae327.
The role of RET/PTC rearrangement in the clinical outcomes of papillary thyroid cancer (PTC) is controversial and remains to be clearly undefined.
This work aimed to investigate the role of coexisting RET/PTC rearrangement and TERT promoter mutation in the prognosis and therapeutic targeting in PTC.
A total of 669 PTC patients with complete clinical follow-up and genetic data were pooled from thyroid cancer data sets TCGA-THCA, MSK-MetTropism, and MSK-IMPACT, from whom 163 patients (112 women and 47 men, 4 unknown) with wild-type (WT) BRAF/RAS were identified, with a median age (interquartile range [IQR]) of 46.00 (33.00-61.00) years and a median follow-up time (IQR) of 16.13 (8.09-27.91) months for comparative genotype cohort analysis of mortality.
There was a significant concurrence index between RET/PTC and TERT promoter mutations, being 2.040 (95% CI, 1.110-3.747; P = .023). Mortality occurred in 5 of 100 (5%) patients harboring neither mutation, 2 of 18 (11.1%) patients harboring a TERT promoter mutation alone, 0 of 31 (0%) patients harboring a RET/PTC alone, and 7 of 14 (50%) patients harboring both genetic alterations, corresponding to hazard ratios (95% CI) of 1 (reference), 2.469 (0.405-14.022), 3.296e-09 (0-inf), and 9.019 (2.635-30.870), respectively, which remained essentially unchanged after adjustment for patient race, sex, and age. Similar results were observed with BRAF/RAS and TERT promoter mutations. Mechanistically, RET/PTC used the MAP kinase pathway to upregulate the mutated TERT, but not the WT TERT, and, correspondingly, targeting RET and MEK could suppress mutated TERT but not the WT TERT.
Coexisting RET/PTC and TERT promoter mutation identify PTC as a unique clinical entity with high mortality, providing new implications for genetic-based prognostication and potential therapeutic targeting of RET and MEK guided by RET/PTC and TERT status.
RET/PTC 重排对甲状腺乳头状癌（PTC）临床结局的作用存在争议，仍未明确界定。
本研究旨在探讨共存的 RET/PTC 重排和 TERT 启动子突变在 PTC 预后和治疗靶向中的作用。
从 TCGA-THCA、MSK-MetTropism 和 MSK-IMPACT 甲状腺癌数据集中汇集了 669 例具有完整临床随访和遗传数据的 PTC 患者，其中 163 例（112 例女性和 47 例男性，4 例未知）具有野生型（WT）BRAF/RAS，中位年龄（四分位距 [IQR]）为 46.00（33.00-61.00），中位随访时间（IQR）为 16.13（8.09-27.91），用于比较死亡率的基因型队列分析。
RET/PTC 和 TERT 启动子突变之间存在显著的共存指数，为 2.040（95%CI，1.110-3.747；P =.023）。未发生突变的 100 例患者中有 5 例（5%）发生死亡，单独发生 TERT 启动子突变的 18 例患者中有 2 例（11.1%），单独发生 RET/PTC 突变的 31 例患者中无一例（0%），同时发生两种遗传改变的 14 例患者中有 7 例（50%）发生死亡，相应的风险比（95%CI）分别为 1（参考）、2.469（0.405-14.022）、3.296e-09（0-inf）和 9.019（2.635-30.870），在调整患者种族、性别和年龄后基本保持不变。BRAF/RAS 和 TERT 启动子突变也得到了类似的结果。在机制上，RET/PTC 利用 MAP 激酶通路上调突变的 TERT，但不上调 WT TERT，相应地，靶向 RET 和 MEK 可以抑制突变的 TERT，但不抑制 WT TERT。
共存的 RET/PTC 和 TERT 启动子突变将 PTC 确定为一种具有高死亡率的独特临床实体，为基于遗传的预后预测和 RET 和 MEK 指导的潜在治疗靶向提供了新的意义，这些靶向策略基于 RET/PTC 和 TERT 状态。
