Department of Oncology-Pathology and Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
Cancer. 2014 Oct 1;120(19):2965-79. doi: 10.1002/cncr.28800. Epub 2014 Jun 4.
The telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have been found in many malignancies, including in thyroid carcinomas. However, it is unclear how early these mutations occur in thyroid tumorigenesis.
The study included primary tumors from 58 patients initially diagnosed with follicular thyroid adenoma (FTA), a benign entity, 18 with atypical FTA (AFTA) having an uncertain malignant potential, and 52 with follicular thyroid carcinoma (FTC). Sanger sequencing was used to investigate the mutational status of the TERT promoter. Telomere length and TERT messenger RNA (mRNA) expression were determined using quantitative polymerase chain reaction (PCR). Telomerase activity was assessed using a Telomerase PCR enzyme-linked immunosorbent assay kit.
The C228T mutation was identified in 1 of 58 FTA (2%) and 3 of 18 AFTA (17%) samples. These 4 tumors all expressed TERT mRNA and telomerase activity, whereas the majority of C228T-negative adenomas lacked TERT expression (C228T versus wild-type, P = .008). The C228T mutation was associated with NRAS gene mutations (P = .016). The patient with C228T-mutated FTA later developed a scar recurrence and died of FTC, whereas none of the remaining 57 patients with FTA had recurrence. No recurrence occurred in 3 patients with AFTA who carried C228T during the follow-up period (36-285 months). Nine of the 52 FTCs (17%) exhibited the TERT mutation (8 of 9 C228T and 1 of 9 C250T), and the presence of the mutation was associated with shorter patient survival.
TERT promoter mutations may occur as an early genetic event in thyroid follicular tumors that have not developed malignant features on routine histopathological workup.
端粒酶逆转录酶（TERT）启动子突变 C228T 和 C250T 已在许多恶性肿瘤中发现，包括甲状腺癌。然而，这些突变在甲状腺肿瘤发生的早期是如何发生的尚不清楚。
本研究纳入了 58 例最初诊断为滤泡状甲状腺腺瘤（FTA）的患者的原发肿瘤，这是一种良性实体瘤；18 例具有不确定恶性潜能的不典型 FTA（AFTA）；52 例滤泡状甲状腺癌（FTC）。采用 Sanger 测序法检测 TERT 启动子的突变状态。采用实时定量聚合酶链反应（PCR）法检测端粒长度和 TERT 信使 RNA（mRNA）表达。采用端粒酶 PCR 酶联免疫吸附试验试剂盒检测端粒酶活性。
1 例 FTA（2%）和 3 例 AFTA（17%）样本中发现 C228T 突变。这 4 例肿瘤均表达 TERT mRNA 和端粒酶活性，而大多数 C228T 阴性腺瘤缺乏 TERT 表达（C228T 与野生型相比，P=0.008）。C228T 突变与 NRAS 基因突变相关（P=0.016）。携带 C228T 的 FTA 患者后来发生瘢痕复发并死于 FTC，而其余 57 例 FTA 患者均无复发。在随访期间（36-285 个月）携带 C228T 的 3 例 AFTA 患者无复发。52 例 FTC 中有 9 例（17%）显示 TERT 突变（9 例中的 8 例为 C228T，9 例中的 1 例为 C250T），突变的存在与患者生存时间缩短相关。
TERT 启动子突变可能是甲状腺滤泡性肿瘤中一种早期遗传事件，在常规组织病理学检查中尚未出现恶性特征。
