For years, molecular pathologists have focused on a dangerous duo. The BRAF V600E mutation, found in about 45 to 60 percent of papillary thyroid cancers, drives tumor growth through the MAPK signaling pathway. Somatic mutations in the promoter of the TERT gene, which encodes telomerase reverse transcriptase, are rarer but potent. When both alterations coexist, the prognosis is grim: landmark work by Xing and colleagues in 2014 showed that patients carrying both mutations had recurrence rates exceeding 68 percent, with a hazard ratio of 8.51 compared to patients without either mutation. The mechanism is elegant. BRAF-driven MAPK activation upregulates FOS, which activates the GABPA-GABPB complex that selectively binds the mutant TERT promoter, creating a feedforward loop of telomerase overexpression and cellular immortalization.

What happens when TERT promoter mutations appear alone, without BRAF? This question has remained surprisingly underexplored, and a team led by Bing Guan at Suzhou BenQ Medical Center in China set out to answer it using publicly available genomic data. Their approach was straightforward. They mined The Cancer Genome Atlas thyroid carcinoma cohort, identified 49 patients with both BRAF and TERT promoter mutation data plus progression-free interval endpoints, and stratified them into four groups: BRAF-negative/TERTp-negative, BRAF-positive/TERTp-negative, BRAF-negative/TERTp-positive, and BRAF-positive/TERTp-positive. They then compared survival outcomes using Kaplan-Meier analysis and Cox proportional hazards regression.

The results were striking. Overall log-rank analysis revealed significant differences in progression-free interval across the four subgroups, with a p-value below 0.001. The BRAF-negative/TERTp-negative group, comprising 33 patients or 67.3 percent of the cohort, showed no progression events at all, with median progression-free interval not reached. The BRAF-positive/TERTp-negative group, with 6 patients, also fared relatively well, with only 2 events and median progression-free interval not reached. But the two TERTp-mutant subgroups told a different story.

The most unexpected finding came from the BRAF-negative/TERTp-positive group. Despite containing only 5 patients, this subgroup showed the worst prognosis of all, with 3 of 5 patients experiencing disease progression, a 60 percent progression rate, and a median progression-free interval of just 5.7 months. In contrast, the BRAF-positive/TERTp-positive group had only 1 event among 5 patients, with a median progression-free interval of 17.5 months. Univariable Cox regression identified BRAF-negative/TERTp-positive status as the strongest adverse predictor, with a hazard ratio of 9.57 and a 95 percent confidence interval spanning 2.02 to 45.25, yielding a p-value of 0.004. This association remained significant after adjustment for age at diagnosis, with an adjusted hazard ratio of 8.38 and a p-value of 0.010.

These findings partially diverge from the prevailing paradigm. The established model holds that the synergistic combination of BRAF and TERT promoter mutations confers the worst prognosis, and the 2014 Xing study, which enrolled 507 patients with 35 dual-mutant cases and 24 months of median follow-up, provided adequate statistical power to detect that synergy. The current analysis, by contrast, found that the isolated TERTp group showed a numerically worse outcome than the dual-mutant group, though the authors are careful to emphasize that this should not be interpreted as contradicting the dual-mutation model. With only 5 patients per TERTp-mutant subgroup and a total of 6 progression events, the Cox models have limited statistical power, and the wide confidence intervals reflect this imprecision directly. The non-significance of the BRAF-positive/TERTp-positive group, with a hazard ratio of 2.88 and a p-value of 0.318, almost certainly reflects type II error rather than a true biological reversal of the established risk hierarchy. A single additional event in that subgroup would substantially alter the hazard ratio estimate.

Recognizing the fragility of small-sample Cox regression, the authors took additional precautions. Because the BRAF-negative/TERTp-negative reference group contained no progression events, standard Cox regression exhibited complete separation and could not produce finite estimates. The team therefore used ridge-penalized Cox regression with a penalizer of 0.1 for primary parameter estimation, and applied Firth’s penalized likelihood correction with a penalizer of 0.05 as a sensitivity analysis to assess small-sample bias. The Firth-corrected estimate yielded a hazard ratio of 16.93 with a 95 percent confidence interval of 2.95 to 97.17 and a p-value of 0.0015, remaining statistically significant and in the same direction as the primary estimate. This suggests that the qualitative conclusion of elevated risk associated with isolated TERT promoter mutation is not solely an artifact of small-sample bias, though the magnitude of the effect remains imprecisely estimated.

To provide biological context, the researchers turned to a second dataset. They analyzed GSE33630, a microarray dataset comprising 58 papillary thyroid carcinoma samples, of which 8 carried BRAF V600E mutations and 34 were BRAF wild-type. Differential expression analysis identified 42 genes with statistically significant differences between the two groups at a false discovery rate below 0.05, comprising 17 upregulated and 25 downregulated transcripts in BRAF-mutant tumors. Among the most notable findings, PCDH20, a protocadherin tumor suppressor that antagonizes Wnt/beta-catenin signaling and suppresses epithelial-mesenchymal transition, was downregulated with a log fold change of -1.54. HES1, a canonical Notch pathway target involved in thyroid differentiation, was also downregulated. TLR2, which plays a key role in innate immune responses, and LGALS3BP were similarly reduced, suggesting impaired immune surveillance in BRAF-mutant tumors. On the other side, DAPK2, a pro-apoptotic serine/threonine kinase, was upregulated with a log fold change of +1.14, possibly as a compensatory response to oncogenic MAPK signaling, though sustained MAPK activation can paradoxically uncouple DAPK2 from its apoptotic function and promote tumor survival.

The authors acknowledge important limitations. The TCGA cohort was not prospectively designed for survival analysis, and selection biases may affect the representation and follow-up of different molecular subgroups. Clinical management differences may also play a role: patients known to carry both BRAF and TERT promoter mutations may have received more aggressive initial therapy, including total thyroidectomy, radioiodine ablation, and external beam radiotherapy, which could partially attenuate observed event rates, while BRAF-negative/TERTp-positive patients may have been under-treated if the absence of BRAF mutation led to lower-risk clinical classification. Furthermore, the progression-free interval endpoint used in this study, standardized by the TCGA Pan-Cancer Clinical Data Resource, differs from the tumor recurrence endpoint used in the 2014 Xing study, and these endpoints are not directly interchangeable. The GSE33630 dataset, collected in 2012 before the identification of TERT promoter mutations, lacks TERTp annotation, preventing TERTp-stratified transcriptomic analysis.

Despite these caveats, the biological plausibility of the finding is compelling. TERT promoter mutations, predominantly the C228T and C250T substitutions, create de novo ETS transcription factor binding sites in the TERT promoter, leading to enhanced telomerase expression and telomere maintenance, which promotes cellular immortalization. In the absence of BRAF-driven MAPK activation, TERTp-mutant tumors may rely on alternative oncogenic cooperators, such as RAS mutations, receptor tyrosine kinase fusions, or epigenetic reprogramming, to drive aggressive behavior. Identifying these cooperating alterations represents an important priority for future research. The authors propose that routine TERT promoter sequencing in papillary thyroid carcinoma may have prognostic value even in the absence of BRAF mutation, and they call for validation in larger prospective cohorts with comprehensive molecular annotation. If confirmed, the finding could reshape how clinicians risk-stratify patients whose tumors lack the more familiar BRAF alteration, potentially catching a hidden high-risk group before disease progression begins.

Subject of Research: Prognostic impact of isolated TERT promoter mutation in papillary thyroid carcinoma

Article Title: 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

Article References: Guan, B., Zhou, R., Zhang, S., Chen, Y., Li, L., & He, P. (2026). 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. Frontiers in Endocrinology, 17, Article 1881969. https://doi.org/10.3389/fendo.2026.1881969

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1881969

Keywords: papillary thyroid carcinoma, TERT promoter mutation, BRAF V600E, TCGA, progression-free interval, Cox regression, GSE33630, differential gene expression, PCDH20, DAPK2, prognosis, molecular risk stratification