BRAF V600E and TERT Promoter Mutations Cooperatively Identify the Most Aggressive Papillary Thyroid Cancer With Highest Recurrence

Purpose To investigate the prognostic value of the BRAF V600E mutation and the recently identified TERT promoter mutation chr5:1,295,228C>T (C228T), individually and in their coexistence, in papillary thyroid cancer (PTC). Patients and Methods We performed a retrospective study of the relationship of BRAF and TERT C228T mutations with clinicopathologic outcomes of PTC in 507 patients (365 women and 142 men) age 45.9 ± 14.0 years (mean ± SD) with a median follow-up of 24 months (interquartile range, 8 to 78 months). Results Coexisting BRAF V600E and TERT C228T mutations were more commonly associated with high-risk clinicopathologic characteristics of PTC than they were individually. Tumor recurrence rates were 25.8% (50 of 194;77.60 recurrences per 1,000 person-years; 95% CI, 58.81 to 102.38) versus 9.6% (30 of 313; 22.88 recurrences per 1,000 person-years; 95% CI, 16.00 to 32.72) in BRAF mutation–positive versus –negative patients (hazard ratio [HR], 3.22; 95% CI, 2.05 to 5.07) and 47.5% (29 of 61; 108.55 recurrences per 1,000 person-years; 95% CI, 75.43 to 156.20) versus 11.4% (51 of 446; 30.21 recurrences per 1,000 person-years; 95% CI, 22.96 to 39.74) in TERT mutation–positive versus –negative patients (HR, 3.46; 95% CI, 2.19 to 5.45). Recurrence rates were 68.6% (24 of 35; 211.76 recurrences per 1,000 person-years; 95% CI, 141.94 to 315.94) versus 8.7% (25 of 287; 21.60 recurrences per 1,000 person-years; 95% CI, 14.59 to 31.97) in patients harboring both mutations versus patients harboring neither mutation (HR, 8.51; 95% CI, 4.84 to 14.97), which remained significant after clinicopathologic cofactor adjustments. Disease-free patient survival curves displayed a moderate decline with BRAF V600E or TERT C228T alone but a sharp decline with two coexisting mutations. Conclusion Coexisting BRAF V600E and TERT C228T mutations form a novel genetic background that defines PTC with the worst clinicopathologic outcomes, providing unique prognostic and therapeutic implications.

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The Genetic Duet of BRAF V600E and TERT Promoter Mutations Robustly Predicts Loss of Radioiodine Avidity in Recurrent Papillary Thyroid Cancer

Journal of Nuclear Medicine ◽

10.2967/jnumed.119.227652 ◽

2019 ◽

Vol 61 (2) ◽

pp. 177-182 ◽

Cited By ~ 8

Author(s):

Jiajun Liu ◽

Rengyun Liu ◽

Xiaopei Shen ◽

Guangwu Zhu ◽

Biao Li ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Braf V600e ◽

Papillary Thyroid ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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Mortality Risk Stratification by Combining BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Cancer

JAMA Oncology ◽

10.1001/jamaoncol.2016.3288 ◽

2017 ◽

Vol 3 (2) ◽

pp. 202 ◽

Cited By ~ 81

Author(s):

Rengyun Liu ◽

Justin Bishop ◽

Guangwu Zhu ◽

Tao Zhang ◽

Paul W. Ladenson ◽

...

Keyword(s):

Thyroid Cancer ◽

Risk Stratification ◽

Papillary Thyroid Cancer ◽

Mortality Risk ◽

Braf V600e ◽

Papillary Thyroid ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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Coexistence of the BRAF V600E and TERT promoter mutations and their impact on response to therapy and final outcome of papillary thyroid cancer

Endocrine Abstracts ◽

10.1530/endoabs.63.gp82 ◽

2019 ◽

Author(s):

Tomasz Trybek ◽

Agnieszka Walczyk ◽

Danuta Gęsior-Perczak ◽

Iwona Pałyga ◽

Estera Mikina ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Response To Therapy ◽

Final Outcome ◽

Braf V600e ◽

Papillary Thyroid ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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In papillary thyroid cancer TERT promoter mutations have a worst impact on outcome than BRAF mutations

Endocrine Abstracts ◽

10.1530/endoabs.37.gp.24.02 ◽

2015 ◽

Author(s):

Marina Muzza ◽

Carla Colombo ◽

Maria Carla Proverbio ◽

Stefania Rossi ◽

Delfina Tosi ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Papillary Thyroid ◽

Braf Mutations ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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Impact of BRAF V600E and TERT Promoter Mutations on Response to Therapy in Papillary Thyroid Cancer

Endocrinology ◽

10.1210/en.2019-00315 ◽

2019 ◽

Vol 160 (10) ◽

pp. 2328-2338 ◽

Cited By ~ 5

Author(s):

Tomasz Trybek ◽

Agnieszka Walczyk ◽

Danuta Gąsior-Perczak ◽

Iwona Pałyga ◽

Estera Mikina ◽

...

Keyword(s):

Thyroid Cancer ◽

Response To Therapy ◽

Braf V600e ◽

Papillary Thyroid ◽

Tumor Node Metastasis ◽

Node Metastasis ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

Abstract In this study, we examined the relationship between coexisting BRAF V600E and TERT promoter mutations in papillary thyroid cancer (PTC) and response to therapy. PTC cases (n = 568) with known BRAF and TERT status, diagnosed from 2000 to 2012 and actively monitored at one institution, were reviewed retrospectively. Associations between BRAF V600E and TERT promoter mutations and clinicopathological features, Tumor-Node-Metastasis stage, initial risk, response to therapy, follow-up, and final disease outcome were assessed according to American Thyroid Association 2015 criteria and the American Joint Committee on Cancer/Tumor-Node-Metastasis (8th edition) staging system. Median follow-up was 120 months. TERT promoter mutations (any type) were detected in 13.5% (77/568) of PTC cases with known BRAF status. The C228T and C250T TERT hotspot mutations were found in 54 (9.5%) and 23 (4%) patients, respectively, and 22 other TERT promoter alterations were identified. Coexisting BRAF V600E and TERT hotspot promoter mutations were detected in 9.5% (54/568) of patients, and significantly associated with older patient age (P = 0.001), gross extrathyroidal extension (P = 0.003), tumor stage pT3-4 (P = 0.005), stage II to IV (P = 0.019), intermediate or high initial risk (P = 0.003), worse than excellent response to primary therapy (P = 0.045), recurrence (P = 0.015), and final outcome of no remission (P = 0.014). We conclude that coexisting BRAF V600E and TERT mutations in patients with PTC are associated with poor initial prognostic factors and clinical course and may be useful for predicting a worse response to therapy, recurrence, and poorer outcome than in patients without the above mutations.

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Clinical and therapeutic implications of Sprouty2 feedback dysregulation in BRAF V600E-mutation-positive papillary thyroid cancer

Surgery ◽

10.1016/j.surg.2013.06.024 ◽

2013 ◽

Vol 154 (6) ◽

pp. 1239-1245 ◽

Cited By ~ 8

Author(s):

Linda A. Dultz ◽

Shumon Dhar ◽

Jennifer B. Ogilvie ◽

Keith S. Heller ◽

Dafna Bar-Sagi ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Therapeutic Implications

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Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2014.56.8253 ◽

2015 ◽

Vol 33 (1) ◽

pp. 42-50 ◽

Cited By ~ 238

Author(s):

Mingzhao Xing ◽

Ali S. Alzahrani ◽

Kathryn A. Carson ◽

Young Kee Shong ◽

Tae Yong Kim ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Multicenter Study ◽

Braf Mutation ◽

Prognostic Value ◽

Braf V600e Mutation ◽

Braf V600e ◽

Disease Stage ◽

Papillary Thyroid ◽

Recurrence Rates

Purpose To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). Patients and Methods This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). Results The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation–positive and 11.6% (125 of 1,082) of BRAF V600E mutation–negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation–positive versus –negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation–positive versus –negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. Conclusion This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

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THE RELATIONSHIP OF THE BRAF-V600E MUTATION WITH THE EXPRESSION OF TRANSCRIPTIONAL, GROWTH FACTORS, COMPONENTS OF THE AKT / M-TOR SIGNALING PATHWAY IN THE TISSUE OF PAPILLARY THYROID CANCER

Problems in oncology ◽

10.37469/0507-3758-2019-65-4-608-613 ◽

2019 ◽

Vol 65 (4) ◽

pp. 608-613

Author(s):

Lyudmila Spirina ◽

Svetlana Chizhevskaya ◽

Irina Kondakova ◽

Yevgeniy Choynzonov

Keyword(s):

Transcription Factors ◽

Thyroid Cancer ◽

Growth Factors ◽

Signaling Pathway ◽

Papillary Thyroid Cancer ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Tor Signaling ◽

Relationship Of

One of the initiating mutations in the development of thyroid cancer is BRAF-V600E, which leads to the various signaling cascades activation and changes in the production of transcription and growth factors. It is known that papillary thyroid cancer is characterized by activation of the expression of transcription factors NF-kB and HIF-2a and AKT/m-TOR signaling cascade. However, the relationship of the studied molecular markers in patients with the wild and mutant BRAF gene has not yet been studied. The aim of the work was to study the expression of transcription factors NF-65B p65 and NF-kB p50, HIF-1a, HIF-2a, growth factors VEGF, CAIX and VEGFR2, components of the AKT/m-TOR signaling pathway in patients with thyroid papillary cancer depending on the presence of mutations BRAF-V600E. Material and methods. It was included 40 patients with papillary thyroid cancer with the stage of the tumor process T1-4N0-2M0. The expression of the indicators was determined by real-time PCR. BRAF-V600E mutation was revealed by allele-specific PCR in real-time. Results and discussion. It was found that patients with the absence and presence of the BRAF-V600E mutation had similar clinical and morphological parameters of the disease, which was accompanied by a change in the molecular-biological characteristics of the tumor. The presence of the mutant form of the gene in the tumor led to a decrease in the AKT, cRAF, GSK-3P kinases mRNA levels and the overexpression of NF-kB p65, HIF-1 and VEGF. Conclusion. Patients with papillary thyroid cancer have no differences in the clinical and morphological characteristics of the disease, depending on the status of the BRAF-V600E gene, is characteristic. It was identified biological parameters associated with this somatic mutation. An increase in the mRNA level of growth and transcription factors was observed with a decrease in the activity of the AKT / m-TOR signaling pathway.

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BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djx227 ◽

2017 ◽

Vol 110 (4) ◽

pp. 362-370 ◽

Cited By ~ 21

Author(s):

Yueye Huang ◽

Shen Qu ◽

Guangwu Zhu ◽

Fei Wang ◽

Rengyun Liu ◽

...

Keyword(s):

Thyroid Cancer ◽

Risk Stratification ◽

Papillary Thyroid Cancer ◽

Braf Mutation ◽

Hazard Ratio ◽

Braf V600e ◽

Independent Effect ◽

Papillary Thyroid ◽

Wild Type ◽

Recurrence Rates

Abstract Background Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. Methods A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow–up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher’s exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. Results Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. Conclusions BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.

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