Xu Yiyi, Gao Jiwei, Wang Na, Zedenius Jan, Nilsson Inga-Lena, Lui Weng-Onn, Xu Dawei, Juhlin C Christofer, Larsson Catharina, Mu Ninni
Department of Oncology-Pathology, Karolinska Institutet, Stockholm SE-171 64, Sweden.
The Cancer Hospital of the University of Chinese Academy of Sciences, (Zhejiang Cancer Hospital), Hangzhou 310022, China.
J Clin Endocrinol Metab. 2025 Feb 18;110(3):693-705. doi: 10.1210/clinem/dgae589.
BRAFV600E and TERT promoter mutations in papillary thyroid carcinoma (PTC) have a synergistic effect on prognosis. This effect is believed to arise from MAPK activation triggered by BRAFV600E, leading to the upregulation of ETS transcription factors that bind to the mutant TERT promoter.
To explore the role of ETS factors in relation to clinical features, BRAFV600E, and TERT promoter mutations in PTC.
Transcriptomic data for 28 ETS factors were analyzed in the PTC cohort of The Cancer Genome Atlas (n = 399) and subsequently validated in a local cohort (n = 93). In vitro experiments were performed to investigate the regulatory role in relation to BRAFV600E and TERT expression.
The Cancer Genome Atlas identified ETS1, ERG, FLI1, GABPA, EHF, ETV6, and SPDEF as differentially expressed genes between stages I + II and III + IV. In both cohorts, EHF was consistently associated with adverse clinical features, BRAFV600E and TERT promoter mutation/expression. Notably, in BRAFV600E mutated PTC, high EHF expression was associated with shorter disease-free survival. Cases harboring concurrent BRAFV600E, TERT promoter mutations, and high EHF expression exhibited the shortest disease-free survival. In cells harboring concurrent BRAFV600E and TERT promoter mutation, overexpression of EHF significantly increased TERT expression, whereas knockdown or pharmacological inhibition of BRAF significantly decreased both EHF and TERT expression. In addition, chromatin immunoprecipitation and quantitative PCR analysis suggested a potential binding of EHF in TERT promoter mutant cells but not in TERT promoter wild-type cells.
The ETS transcription factor EHF is associated with poor prognosis in PTC. This is potentially mediated by BRAF-induced upregulation of EHF, which in turn increases TERT expression in TERT promoter mutated cells.
甲状腺乳头状癌（PTC）中的BRAFV600E和端粒酶逆转录酶（TERT）启动子突变对预后具有协同作用。据信这种作用源于BRAFV600E触发的丝裂原活化蛋白激酶（MAPK）激活，导致与突变TERT启动子结合的ETS转录因子上调。
探讨ETS因子在PTC临床特征、BRAFV600E和TERT启动子突变方面的作用。
在癌症基因组图谱（TCGA）的PTC队列（n = 399）中分析了28种ETS因子的转录组数据，随后在一个本地队列（n = 93）中进行了验证。进行体外实验以研究其与BRAFV600E和TERT表达相关的调控作用。
TCGA鉴定出ETS1、ERG、FLI1、GABPA、EHF、ETV6和SPDEF为I + II期与III + IV期之间的差异表达基因。在两个队列中，EHF均与不良临床特征、BRAFV600E和TERT启动子突变/表达持续相关。值得注意的是，在BRAFV600E突变的PTC中，高EHF表达与无病生存期缩短相关。同时存在BRAFV600E、TERT启动子突变和高EHF表达的病例表现出最短的无病生存期。在同时存在BRAFV600E和TERT启动子突变的细胞中，EHF的过表达显著增加TERT表达，而BRAF的敲低或药物抑制则显著降低EHF和TERT表达。此外，染色质免疫沉淀和定量PCR分析表明EHF在TERT启动子突变细胞中存在潜在结合，但在TERT启动子野生型细胞中不存在。
ETS转录因子EHF与PTC的不良预后相关。这可能是由BRAF诱导的EHF上调介导的，进而增加了TERT启动子突变细胞中的TERT表达。
