BRAF V600E + TERT mutation

These findings underscore the importance of TERT alterations in aggressive phenotypes and offer insights into molecular mechanisms guiding targeted therapies. Further research is necessary to confirm their significance as diagnostic and prognostic markers in thyroid cancer.

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.

Based on immediate post‐operative ATA risk stratification by histology, appropriate initial TL and TT occurred for all patients with MT low‐ and high‐risk alterations. However, MT intermediate‐risk results (typically BRAF‐like) were associated with histologies in all 3 ATA risk categories. The patients are being followed to monitor for tumor recurrence while additional clinical factors will be explored in order to continue refining optimal initial extent of surgery.

Mice with dedifferentiated tumors treated with 4 weeks of either lenvatinib or dabrafenib/trametinib (dab/tram) for Braf/Arid1a or tipifarnib for Hras/p53 demonstrated tumor progression or stability (% change tumor volume: Braf/Arid1a: vehicle +238. Combination MAPK signaling blockade and angiogenesis inhibition leads to profound anti‐tumor responses across the spectrum of thyroid cancers in GEMMs.

These models constitute useful pre-clinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs. Implications: Telomerase-driven cancer progression activates pathways that can be dissected and perhaps therapeutically exploited.

TERT promoter mutations alone or in combination with BRAFV600E mutation, but not BRAFV600E mutation alone, correlated well with the ATA and TNM staging and predicted development of PD, especially in higher stages of these systems. The combination of high-risk ATA or TNM stage IV with TERT promoter mutations is highly predictive of development of PD predicting PD in 100% of cases with these combinations.

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In this large-scale study evaluating PD-L1 expression in ATC specimens, most of the ATCs were PD-L1-positive, which provides a rationale for immunotherapy in this aggressive malignancy. The positivity rate was lower in small biopsy specimens, having implications for clinical decision-making and formulation of management guidelines. PD-L1 expression did not correlate with BRAF V600E or TERT promoter mutation status.

Trabecular pattern identification by visual assessment shows a moderate degree of inter-observer reproducibility. The patten is significantly associated with BRAF V600e mutations suggesting aggressive behavior potentially derives from consequences of this specific mutation.

Sensitive molecular assays have been established to specifically detect and quantify VAFs of BRAF V600E and TERT promoter variants using the dPCR approach. Quantitative molecular assays may facilitate definitive malignancy diagnoses among patients with thyroid nodules harboring such variants, and a high VAF of each variant alone or their coexistence at various VAFs increases the association with unfavourable clinico‐pathological features of the tumor.

Braf+Tert animals partially responded to MAPK pathway inhibition (dabrafenib plus trametinib), showing that this crucial pathway remains relevant in these specimens. These pointed to key cancer functional processes that might inform new routes for therapeutic intervention in telomerase-mediated aggressive thyroid cancers. Conclusion These cancer models of telomerase reactivation provide excellent pre-clinical settings to understand the regulatory mechanisms and biological underpinnings of TPM-induced progression of thyroid (and other tumors) to aggressive disease, and to explore novel therapeutic strategies.

Braf+Tert animals partially responded to MAPK pathway inhibition (dabrafenib plus trametinib), showing that MAPK signaling remains relevant in these specimens. Interestingly, RNA sequencing of Tert-reactivated murine thyroid tumors showed unique transcriptomic profiles (compared to BrafV600E alone), suggesting that downstream effects, other than the canonical Tert-mediated telomere maintenance, operate in cancers harboring TPMs. These cancer models of telomerase reactivation provide excellent pre-clinical settings to understand the regulatory mechanisms and biological underpinnings of TPM-induced progression of thyroid and other tumors, and to explore novel therapeutic strategies.

BRAFV600E, TERT and RET mutations were associated with aggressive thyroid cancers. These findings may help thyroid specialists better identify aggressive thyroid nodules associated with different Bethesda categories and to tailor patient treatment.

Combining cytology with ddPCR analysis of TERT, BRAF and RAS mutations can improve the diagnostic accuracy of thyroid FNABs.