Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Thyroid. 2020 Nov;30(11):1589-1600. doi: 10.1089/thy.2019.0459. Epub 2020 May 19.
Although most differentiated thyroid carcinomas (DTCs) have indolent behavior, DTCs with distant metastasis have a poor prognosis. However, there are no validated markers that predict the risk of distant metastasis and the prognosis of DTC. We aimed to develop a genetic classifier for predicting the outcomes of DTC patients with distant metastases. Targeted deep sequencing of 157 cancer-related genes was performed for 61 DTCs with distant metastases. A candidate mutation was validated with independent thyroid cancer samples using digital polymerase chain reaction. The most frequently mutated gene in the 61 DTCs was ( = 31, 51%), followed by promoter ( = 28, 46%), ( = 13, 11%), promoter ( = 6, 10%), and ( = 6, 10%) mutations. promoter mutations were more common in the radioactive iodine (RAI)-refractory cases ( = 0.003). Losses of 9q and 11q were associated with RAI-refractory disease ( = 0.002) and cancer-specific mortality ( = 0.028), respectively. In multivariate analysis, bone metastasis (adjusted odds ratio [aOR] = 15.17, 95% confidence interval [CI 3.38-68.06], < 0.001) and at least one mutation in the promoter, the promoter, or (aOR = 7.64 [CI 1.78-32.76], = 0.006) remained significant factors associated with RAI-refractoriness. In independently collected papillary thyroid carcinomas without initial distant metastasis ( = 75), a promoter mutation was only found in one case that developed distant metastasis during the follow-up period. We developed a genetic classifier consisting of , , the promoter, the promoter, and for categorizing the prognosis of patients with DTC with distant metastasis. In the poor-prognosis group, 61% of the patients were RAI-refractory and death occurred in 21% during the follow-up. In the intermediate-prognosis group, 29% were RAI-refractory, but no death occurred. In the good-prognosis group, all patients were RAI-responsive and no death occurred. Mutations in the promoter are a novel genetic marker of aggressive DTC. Our genetic classifier can be useful for predicting RAI-refractory disease and poor prognosis in DTC patients with distant metastases.
尽管大多数分化型甲状腺癌 (DTC) 具有惰性行为，但有远处转移的 DTC 预后较差。然而，目前还没有经过验证的标志物可以预测 DTC 远处转移的风险和预后。我们旨在开发一种基因分类器，以预测有远处转移的 DTC 患者的结局。对 61 例有远处转移的 DTC 进行了 157 个癌症相关基因的靶向深度测序。使用数字聚合酶链反应，用独立的甲状腺癌样本验证候选突变。在 61 例 DTC 中最常突变的基因是 （ = 31，51%），其次是 启动子（ = 28，46%）、 （ = 13，11%）、 启动子（ = 6，10%）和 （ = 6，10%）突变。 启动子突变在放射性碘 (RAI) 难治性病例中更为常见（ = 0.003）。9q 和 11q 的缺失与 RAI 难治性疾病（ = 0.002）和癌症特异性死亡率（ = 0.028）相关。在多变量分析中，骨转移（调整后的优势比 [aOR] = 15.17，95%置信区间 [CI 3.38-68.06]， < 0.001）和 启动子、 启动子或 （aOR = 7.64 [CI 1.78-32.76]， = 0.006）中至少有一个突变仍然是与 RAI 难治性相关的显著因素。在独立收集的无初始远处转移的甲状腺乳头状癌中（ = 75），在随访期间发生远处转移的一个病例中仅发现了 启动子突变。我们开发了一种由 、 、 启动子、 启动子和 组成的基因分类器，用于对有远处转移的 DTC 患者的预后进行分类。在预后不良组中，有 61%的患者为 RAI 难治性，随访期间有 21%的患者死亡。在预后中等组中，有 29%的患者为 RAI 难治性，但无死亡。在预后良好组中，所有患者均对 RAI 有反应，且无死亡。 启动子中的突变是侵袭性 DTC 的一种新的遗传标志物。我们的基因分类器可用于预测有远处转移的 DTC 患者的 RAI 难治性疾病和不良预后。
