Background/Objectives:RASmutations are among the most common genetic alterations in thyroid cancer and are generally associated with less aggressive behavior. However, when co-occurring withTERT(telomerase reverse transcriptase) promoter mutations, known markers of poor prognosis, tumors exhibit markedly more aggressive features. The allele frequency (AF) ofRASmay serve as a potential indicator of clonal dominance and the likelihood of additional high-risk mutations, such asTERTmutation. This study aims to assess whether a highRASAF correlates with the presence of coexistingTERTpromoter mutations and other molecular alterations. Methods: A retrospective chart review was performed on 111 patients with thyroid nodules harboringRASmutations, either alone or in combination withTERTpromoter mutations. All patients underwent molecular testing with ThyroSeq v3 and subsequent thyroidectomy at McGill University teaching hospitals.RASAF was analyzed in relation toTERTmutation status, nodule size, and other molecular alterations including copy number alterations (CNA) and gene expression profiles (GEP). Results: The meanRASAF was significantly higher in nodules with bothRASandTERTmutations (38.1%) compared to those withRASmutations alone (22.1%) (p= 0.002). Nodules with coexistingTERTmutations were also significantly larger (mean size: 3.7 cm vs. 2.4 cm;p= 0.005). Malignant nodules, regardless ofTERTstatus, showed a trend toward higherRASAF than benign nodules (23.0% vs. 16.3%;p= 0.052). HigherRASAF was also associated with the presence of CNA and/or GEP positivity. Notably, GEP was positive in 100% of nodules with bothRASandTERTmutations, compared to 37.5% inRAS-only nodules (p= 0.002). Conclusions: A highRASAF increases the likelihood of aTERTpromoter mutation and other genetic alterations, highlighting the importance ofRASAF in optimizing patient care and management.
背景/目的：RAS突变是甲状腺癌中最常见的基因改变之一，通常与较低的侵袭性相关。然而，当与已知预后不良标志物TERT（端粒酶逆转录酶）启动子突变共存时，肿瘤表现出显著更强的侵袭性特征。RAS等位基因频率（AF）可作为克隆优势和存在其他高风险突变（如TERT突变）可能性的潜在指标。本研究旨在评估高RAS AF是否与共存TERT启动子突变及其他分子改变相关。方法：对111例携带RAS突变（单独或与TERT启动子突变共存）的甲状腺结节患者进行回顾性病历分析。所有患者均在麦吉尔大学教学医院接受ThyroSeq v3分子检测及后续甲状腺切除术。分析RAS AF与TERT突变状态、结节大小及其他分子改变（包括拷贝数变异和基因表达谱）的关系。结果：同时存在RAS和TERT突变结节的RAS AF均值（38.1%）显著高于仅存在RAS突变的结节（22.1%）（p=0.002）。共存TERT突变的结节体积也显著更大（平均尺寸：3.7厘米 vs. 2.4厘米；p=0.005）。无论TERT状态如何，恶性结节均呈现比良性结节更高的RAS AF趋势（23.0% vs. 16.3%；p=0.052）。较高的RAS AF还与拷贝数变异和/或基因表达谱阳性相关。值得注意的是，RAS和TERT突变共存结节的基因表达谱阳性率达100%，而仅RAS突变结节为37.5%（p=0.002）。结论：高RAS AF会增加TERT启动子突变及其他基因改变的可能性，凸显了RAS AF在优化患者诊疗管理中的重要性。
HighRASAllele Frequency Signals Increased Risk ofTERTPromoter Mutations in Thyroid Tumors
肿瘤(癌症)患者之家