Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Natl Cancer Inst. 2024 May 8;116(5):694-701. doi: 10.1093/jnci/djad265.
BRAF V600E and TERT promoter alterations are core components in current genetics-based risk assessment for precision management of papillary thyroid cancer. It remains unknown whether this approach could achieve even better precision through a widely recognized prognostic single-nucleotide variation (SNV, formerly SNP), rs2853669T>C, in the TERT promoter.
The genetic status of alterations and SNV were examined by sequencing genomic DNA from papillary thyroid cancer in 608 patients (427 women and 181 men) aged 47 years (interquartile range = 37-57), with a median follow-up time of 75 months (interquartile range = 36-123), and their relationship with clinical outcomes was analyzed. A luciferase reporter assay was performed to examine TERT promoter activities.
TERT promoter alterations showed a strong association with papillary thyroid cancer recurrence in the presence of genotype TT of rs2853669 (adjusted hazard ratio [HR] = 2.12, 95% confidence interval [CI] = 1.10 to 4.12) but not TC/CC (adjusted HR = 1.17, 95% CI = 0.56 to 2.41). TERT and BRAF alterations commonly coexisted and synergistically promoted papillary thyroid cancer recurrence. With this genetic duet, TT of rs2853669 showed a robustly higher disease recurrence than TC/CC (adjusted HR = 14.26, 95% CI = 2.86 to 71.25). Patients with the genetic trio of BRAF V600E, TERT alteration, and TT of rs2853669 had a recurrence of 76.5% vs recurrence of 8.4% with neither variation and with TC/CC (HR = 13.48, 95% CI = 6.44 to 28.21). T allele of rs2853669 strongly increased TERT promoter activities, particularly the variant promoters.
The SNV rs2853669T>C dramatically refines the prognostic power of BRAF V600E and TERT promoter alterations to a higher precision, suggesting the need for including this SNV in the current genetics-based risk prognostication of papillary thyroid cancer.
BRAF V600E 和 TERT 启动子改变是当前基于遗传学的精准管理甲状腺乳头状癌风险评估的核心组成部分。目前尚不清楚这种方法是否可以通过广泛认可的预后单核苷酸变异（SNV，以前称为 SNP）rs2853669T>C 来实现更高的精准度，该 SNP 位于 TERT 启动子中。
通过对 608 例（427 名女性和 181 名男性）年龄为 47 岁（四分位距=37-57）的甲状腺乳头状癌患者的基因组 DNA 进行测序，检测了改变和 SNV 的遗传状态，并分析了它们与临床结果的关系。通过荧光素酶报告基因检测分析 TERT 启动子活性。
rs2853669 的 TT 基因型与甲状腺乳头状癌复发密切相关（调整后的危险比[HR]=2.12，95%置信区间[CI]=1.10-4.12），但 TC/CC 基因型则无此相关性（调整后的 HR=1.17，95% CI=0.56-2.41）。TERT 启动子改变与 BRAF 改变通常共存并协同促进甲状腺乳头状癌的复发。有了这种遗传双重作用，rs2853669 的 TT 基因型比 TC/CC 基因型（调整后的 HR=14.26，95% CI=2.86-71.25）更能显著增加疾病的复发率。具有 BRAF V600E、TERT 改变和 rs2853669TT 遗传三联体的患者复发率为 76.5%，而既无变异又有 TC/CC 基因型的患者复发率为 8.4%（HR=13.48，95% CI=6.44-28.21）。rs2853669 的 T 等位基因强烈增加了 TERT 启动子活性，特别是变体启动子。
SNV rs2853669T>C 显著提高了 BRAF V600E 和 TERT 启动子改变的预后能力，达到了更高的精度，这表明需要将该 SNV 纳入当前基于遗传学的甲状腺乳头状癌风险预测。
