Thyroid Unit, Endocrine division, Hospital de Clínicas de Porto Alegre (HCPA), Brazil.
Medical School, Universidade Federal do Rio Grande do Sul (UFRGS), Brazil.
Endocr Relat Cancer. 2024 Jul 31;31(9). doi: 10.1530/ERC-24-0058. Print 2024 Sep 1.
TERT promoter mutations C228T and C250T are associated with disease aggressiveness and poor clinical outcomes in patients with papillary thyroid carcinomas. However, very little is known about the transcriptional consequences of these mutations and whether they both carry similar oncogenic potential. Here we characterized the transcriptional disturbances and clinical outcomes associated with the presence of each of these two mutations using data derived from The Cancer Genome Atlas. We observed that tumors harboring the C228T mutation (n = 27) exhibited a 16-fold increase in TERT mRNA levels (P = 5.3 × 10-42), whereas C250T tumors (n = 8) showed only a two-fold increase in expression (P = 0.034). The C228T mutation was associated with the activation of signaling pathways controlling the cell cycle, cellular division, and extracellular matrix degradation. Univariate analysis demonstrated that the C228T mutation was associated with older age at diagnosis, large tumor size, lymph node invasion, and distant metastases at diagnosis. The C228T mutation was also associated with worse progression-free interval (PFI) in comparison to WT tumors (HR = 5,04; P < 0.001). This association remained significant in a multivariate analysis (HR = 3.74, P = 0.003) adjusting for BRAF-V600E status and ATA risk group. Our data indicate that TERT promoter mutations C228T and C250T have distinct transcriptional consequences in papillary thyroid carcinoma (PTC), suggesting a greater oncogenic potential for the C228T mutation. TERT promoter mutation C228T may be a useful prognostic marker to identify patients at high risk of distant recurrence. Clinical data for the C250T mutation is still limited, with no evidence up to date to confirm its prognostic significance.
TERT 启动子突变 C228T 和 C250T 与甲状腺乳头癌患者的侵袭性和不良临床结局相关。然而，人们对这些突变的转录后果知之甚少，也不知道它们是否具有相似的致癌潜力。在这里，我们使用来自癌症基因组图谱的数据，描述了这两种突变各自存在时的转录失调和临床结局。我们观察到，携带 C228T 突变的肿瘤（n = 27）的 TERT mRNA 水平增加了 16 倍（P = 5.3 × 10-42），而 C250T 肿瘤（n = 8）的表达仅增加了两倍（P = 0.034）。C228T 突变与控制细胞周期、细胞分裂和细胞外基质降解的信号通路的激活有关。单变量分析表明，C228T 突变与诊断时年龄较大、肿瘤较大、淋巴结侵犯和远处转移有关。与 WT 肿瘤相比，C228T 突变还与无进展生存期（PFI）更差相关（HR = 5.04；P < 0.001）。在多变量分析（调整 BRAF-V600E 状态和 ATA 风险组后，HR = 3.74，P = 0.003）中，这种关联仍然显著。我们的数据表明，TERT 启动子突变 C228T 和 C250T 在甲状腺乳头癌（PTC）中具有不同的转录后果，提示 C228T 突变具有更大的致癌潜力。TERT 启动子突变 C228T 可能是一种有用的预后标志物，可识别出具有远处复发高风险的患者。目前还没有关于 C250T 突变的临床数据，尚无证据证实其预后意义。
