TERT mutation + BRAF V600E

The BRAFV600E and TERT-p double mutation in PTC was significantly associated with relatively old age, larger tumor size, lobulated configuration in tumor margin, papillary excrescences on the cut surface, solid-cut surface, ETE, and high Ki-67 LI. These features are suggestive of the presence of the double mutation and should be analyzed at the molecular level in patients with PTC.

Although the value of preoperative molecular testing for indeterminate nodules (Bethesda III and Bethesda IV) have been analyzed in numerous studies, the impact of preoperative molecular testing on Bethesda V and Bethesda VI thyroid nodules is not adequately described in the current literature. The preoperative recognition of specific molecular mutations, such as BRAFV600E and TERT promoter mutation, might provide more individualized management for thyroid cancer patients by altering the surgical approach and the extent of surgery for patients diagnosed with a more aggressive or iodine-resistant subtype of thyroid cancer.Thyroid cancer is characterized by multiple genetic mutations and alterations and, as a result, preoperative molecular testing of malignant nodules could be a very useful tool for surgeons, enabling them to decide on the most appropriate surgical approach for each patient.

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.

The frequency of TERT promoter mutations was the lowest in this study, compared to previous studies. TERT promoter mutations consistently correlated with aggressive PTCs, and the synergistic effect of both mutations was evident. Specific clinical settings in our institution and in Korea may have led to these distinctive results.

The evolution of molecular testing has reached a stage of personalised incorporation into surgical practice. Guidelines for molecular testing and surgery in WDTC will need to be clearly defined, arguably representing the next chapter in the management of the disease.

These results may indicate that exposure to the mixture of pollutants present in the WTC dust resulted in an excess thyroid cancer risk and potentially more aggressive thyroid cancer, warranting investigating WTC responders on thyroid-associated symptoms during their health check-ups. Future studies should include long-term follow-up to provide important insights in whether thyroid specific survival is negatively affected by WTC dust exposure and whether this is because of the presence of one or more driver mutations.

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.

This case suggests that the "second hit" event is a TP53 mutation. The detection of a TP53 mutation in PTC with an aggressive phenotype may help predict anaplastic transformation.

Papillary thyroid carcinoma with concomitant BRAF-V600E and TERT promoter mutations demonstrated an aggressive course of disease, suggesting the need for a more extensive surgical strategy. RET rearrangement-positive papillary thyroid carcinoma did not affect the clinical outcome, potentially obviating the need for prophylactic lymphadenectomy.

Though it was predominant in PTMC in our study, BRAFV600E mutation could not be a valuable tool to identify high‐risk or tumor progression of PTMC, from a clinical point of view. Instead, tumor size was closely related to aggressiveness. PTMC with ≤5mm should be regarded as a special group and treated specially.

Specific clinical settings in our institution and in Korea may have led to these distinctive results. Prospective multicenter studies with longer follow-up periods are required to establish valuable oncologic outcomes.

We found that BRAF V600E and TERT promoter mutation is significantly correlated with the poor curative effect of RAI therapy in PTC.

Among DTC patients with DM at diagnosis, non-iodine-avid disease is highly prevalent in patients with BVL cancers, particularly with BRAFV600E and TERT promoter mutations, and is associated with an older age. Better strategies are needed to improve RAI treatment response for these patients.

There was no significant difference in recurrence, mortality, and BRAF V600E and TERT promoter mutation between FNMTC and SNMTC, among which 50/60 (83.33%) of FNMTC patients had BRAF V600E mutation and 1/32 (3.13%) had TERT promoter mutation, while the mutation rates of SNMTC were 93/108 (86.11%) and 3/64 (4.69%) (p > 0.05). There was no significant difference in invasiveness and prognosis between FNMTC and SNMTC by biological behavior, patient survival, and molecular level comparison.

This is the first study describing the high prevalence of BRAF and TERT promoter mutations in a carefully selected cohort of RAIR locoregional recurrences of PTC. RAIR tumors showed frequent PD-L1 expression, which may have clinical implications.

Accordingly, dabrafenib insensitivity triggered cross-resistance towards the MEK inhibitor trametinib. Uncoupled from the MAPK pathway, ETS1 expression was further upregulated in the dabrafenib-resistant subline. CONSLUSION: Taken together, our data demonstrate that MAPK-independent ETS transcription factor upregulation is a central mechanism of BRAF inhibitor therapy failure in BRAF -mutated pediatric glioma patients.

The above data supports the classification of high grade non-anaplastic thyroid carcinoma as a single group with two distinct subtypes based on tumor differentiation: HGTC-PDTC and HGTC-nonPDTC.

In conclusion, patients with co-existing BRAF V600E and TERT promoter mutation have a worse prognosis. ARMS-qPCR, the more sensitive method, can be used to identify the early stages of patients with a potentially worse prognosis.