Background BRAF V600E and TERT promoter mutations are core components in current genetic-based risk assessment for precision management of papillary thyroid cancer (PTC). It remains unknown whether this could be refined to even better precision by a widely recognized prognostic single nucleotide polymorphism (SNP), rs2853669T>C, in the TERT promoter. Methods Genetic status of mutations and SNP were examined by sequencing genomic DNA from PTC in 608 patients (427 women and 181 men) aged 47 years (IQR 37-57), with a median follow-up time of 75 months (IQR 36 to 123), and their relationship with clinical outcomes was analyzed. Luciferase reporter assay was performed to examine TERT promoter activities. Results TERT promoter mutations showed a strong association with PTC recurrence in the presence of genotype TT of rs2853669 (adjusted HR = 2.12, 95% CI 1.10-4.12) but not TC/CC (adjusted HR = 1.17, 95% CI 0.56-2.41). TERT and BRAF mutations commonly coexisted and synergistically promoted PTC recurrence. With this genetic duet, TT of rs2853669 showed a robustly higher disease recurrence compared with TC/CC (adjusted HR = 14.26, 95% CI 2.86-71.25). Patients with the genetic trio of BRAF V600E, TERT mutation and TT of rs2853669 had a recurrence of 76.5% vs recurrence of 8.4% with neither mutation and with TC/CC (HR = 13.48, 95% CI 6.44-28.21). T allele of rs2853669 strongly increased TERT promoter, particularly the mutant promoter. Conclusions SNP rs2853669T>C dramatically refines the prognostic power of BRAF V600E and TERT promoter mutations to a higher precision, suggesting the need for including this SNP in the current genetic-based risk prognostication of PTC.

中文翻译：

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BRAF、TERT 突变和 rs2853669TT 基因三重奏在甲状腺乳头状癌侵袭性中的作用

背景 BRAF V600E 和 TERT 启动子突变是当前基于基因的甲状腺乳头状癌 (PTC) 精准管理风险评估的核心组成部分。目前尚不清楚是否可以通过TERT启动子中广泛认可的预后单核苷酸多态性(SNP)rs2853669T＞C将其改进至更高的精度。方法 通过对 608 名年龄 47 岁（IQR 37-57）患者（427 名女性和 181 名男性）的 PTC 基因组 DNA 进行测序，检查突变和 SNP 的遗传状态，中位随访时间为 75 个月（IQR 36 至 123） ），并分析它们与临床结果的关系。进行荧光素酶报告基因测定以检查TERT启动子活性。结果 TERT 启动子突变显示，在 rs2853669 基因型 TT 存在的情况下，与 PTC 复发有很强的相关性（调整后的 HR = 2.12，95% CI 1.10-4.12），但与 TC/CC 无关（调整后的 HR = 1.17，95% CI 0.56-2.41） 。TERT 和 BRAF 突变通常共存并协同促进 PTC 复发。通过这种遗传二重奏，与 TC/CC 相比，rs2853669 的 TT 显示出明显更高的疾病复发率（调整后 HR = 14.26，95% CI 2.86-71.25）。具有 BRAF V600E、TERT 突变和 rs2853669 TT 基因三重奏的患者的复发率为 76.5%，而无突变和 TC/CC 的复发率为 8.4%（HR = 13.48，95% CI 6.44-28.21）。rs2853669 的 T 等位基因强烈增加 TERT 启动子，特别是突变启动子。结论 SNP rs2853669T>C 极大地提高了 BRAF V600E 和 TERT 启动子突变的预后能力，达到更高的精度，表明需要将该 SNP 纳入当前基于遗传的 PTC 风险预测中。