Lefebvre Coralie, Greenspoon Hannah, Payne Kayla E, Steinberg Emily, Tewfik Felicia, Savoia Gianluca, da Silva Sabrina Daniela, Pusztaszeri Marc, Forest Véronique-Isabelle, Payne Richard J
Faculty of Medicine, McGill University, Montreal, QC H3A 2M7, Canada.
Faculty of Arts and Science, Queen's University, Kingston, ON K7L 3N6, Canada.
Cancers (Basel). 2025 Aug 30;17(17):2851. doi: 10.3390/cancers17172851.
BACKGROUND/OBJECTIVES: mutations are among the most common genetic alterations in thyroid cancer and are generally associated with less aggressive behavior. However, when co-occurring with (telomerase reverse transcriptase) promoter mutations, known markers of poor prognosis, tumors exhibit markedly more aggressive features. The allele frequency (AF) of may serve as a potential indicator of clonal dominance and the likelihood of additional high-risk mutations, such as mutation. This study aims to assess whether a high AF correlates with the presence of coexisting promoter mutations and other molecular alterations.
A retrospective chart review was performed on 111 patients with thyroid nodules harboring mutations, either alone or in combination with promoter mutations. All patients underwent molecular testing with ThyroSeq v3 and subsequent thyroidectomy at McGill University teaching hospitals. AF was analyzed in relation to mutation status, nodule size, and other molecular alterations including copy number alterations (CNA) and gene expression profiles (GEP).
The mean AF was significantly higher in nodules with both and mutations (38.1%) compared to those with mutations alone (22.1%) ( = 0.002). Nodules with coexisting mutations were also significantly larger (mean size: 3.7 cm vs. 2.4 cm; = 0.005). Malignant nodules, regardless of status, showed a trend toward higher AF than benign nodules (23.0% vs. 16.3%; = 0.052). Higher AF was also associated with the presence of CNA and/or GEP positivity. Notably, GEP was positive in 100% of nodules with both and mutations, compared to 37.5% in -only nodules ( = 0.002).
A high AF increases the likelihood of a promoter mutation and other genetic alterations, highlighting the importance of AF in optimizing patient care and management.
背景/目的：突变是甲状腺癌中最常见的基因改变之一，通常与侵袭性较低的行为相关。然而，当与TERT（端粒酶逆转录酶）启动子突变同时出现时，TERT启动子突变是预后不良的已知标志物，肿瘤表现出明显更具侵袭性的特征。TERT的等位基因频率（AF）可能作为克隆优势以及其他高危突变（如BRAF突变）可能性的潜在指标。本研究旨在评估高TERT AF是否与共存的TERT启动子突变和其他分子改变的存在相关。
对111例甲状腺结节患者进行回顾性病历审查，这些患者单独或与TERT启动子突变一起存在TERT突变。所有患者在麦吉尔大学教学医院接受了ThyroSeq v3分子检测及随后的甲状腺切除术。分析TERT AF与BRAF突变状态、结节大小以及其他分子改变（包括拷贝数改变（CNA）和基因表达谱（GEP））的关系。
与单独存在BRAF突变的结节（22.1%）相比，同时存在BRAF和TERT突变的结节中TERT的平均AF显著更高（38.1%）（P = 0.002）。共存TERT突变的结节也显著更大（平均大小：3.7 cm对2.4 cm；P = 0.005）。无论BRAF状态如何，恶性结节的TERT AF均有高于良性结节的趋势（23.0%对16.3%；P = 0.052）。较高的TERT AF也与CNA的存在和/或GEP阳性相关。值得注意的是，在同时存在BRAF和TERT突变的结节中，100%的GEP呈阳性，而仅存在BRAF突变的结节中这一比例为37.5%（P = 0.002）。
高TERT AF增加了TERT启动子突变和其他基因改变的可能性，突出了TERT AF在优化患者护理和管理中的重要性。
