Isolated TERT promoter mutation may define a high-risk prognostic subgroup in papillary thyroid carcinoma: an exploratory, hypothesis-generating analysis of TCGA and GSE33630 datasets

Abstract

Background The prognostic value of combined BRAF V600E and TERT promoter (TERTp) mutations in papillary thyroid carcinoma (PTC) has been established in surgical cohorts. However, the independent impact of TERTp mutation in the absence of BRAF mutation remains underexplored, particularly within publicly available genomic datasets. Methods We analyzed 49 PTC patients with available BRAF and TERTp mutation data from The Cancer Genome Atlas (TCGA) Thyroid Carcinoma (THCA) cohort. Patients were stratified into four subgroups: BRAF−/TERTp−, BRAF+/TERTp−, BRAF−/TERTp+, and BRAF+/TERTp+. Progression-free interval (PFI) was compared using Kaplan–Meier analysis and Cox proportional hazards regression. Additionally, differential gene expression analysis was performed using GSE33630 (n = 42 PTC samples) to explore transcriptomic correlates of BRAF mutation. Results Overall log-rank analysis revealed significant PFI differences across the four subgroups (p < 0.001). The BRAF−/TERTp+ group demonstrated the worst prognosis, with 3 of 5 patients experiencing disease progression (median PFI = 5.7 months), compared with no events in the BRAF−/TERTp− group. Univariable Cox regression identified BRAF−/TERTp+ as the strongest adverse predictor (HR = 9.57, 95% CI: 2.02–45.25, p = 0.004), which remained significant after adjustment for age (HR = 8.38, 95% CI: 1.67–42.19, p = 0.010). In GSE33630, 42 differentially expressed genes (DEGs; FDR < 0.05) were identified between BRAF-mutant and wild-type PTC, including downregulation of PCDH20, HES1, and TLR2, and upregulation of DAPK2. Conclusions This hypothesis-generating, exploratory analysis suggests that isolated TERTp mutation may represent an underrecognized high-risk PTC subgroup. The wide confidence intervals reflect the small sample size and limited event counts inherent to this dataset. These preliminary findings warrant validation in larger prospective cohorts with comprehensive molecular annotation.