<i>TERT</i>Promoter Mutations and Their Association with<i>BRAF</i>V600E Mutation and Aggressive Clinicopathological Characteristics of Thyroid Cancer

Liu, Xiaoli; Qu, Shen; Liu, Rengyun; Sheng, Chunjun; Shi, Xiaoguang; Zhu, Guangwu; Murugan, Avaniyapuram Kannan; Guan, Haixia; Yu, Hongyu; Wang, Yangang; Sun, Hui; Shan, Zhongyan; Wang, Teng; Xing, Mingzhao

doi:10.1210/jc.2013-4048

Cited by 261 publications

(236 citation statements)

References 22 publications

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“…Association between TERT and BRAF mutation has been previously reported (24,26,27,33) and it has been proposed that their coexistence may define a more aggressive subgroup of PTC (33). Our results suggest that TERT promoter mutations are associated with the presence of distant metastases independently from the BRAF status, which is not predictive, alone or in association with TERT mutations, with aggressive behavior in our cohort, as previously described (31,32).…”

Section: Discussionsupporting

confidence: 73%

“…These alterations were TERT promoter mutations were also described in thyroid cancer, where C228T represents the most common mutation. The frequency of TERT promoter mutations is quite low in well-differentiated thyroid cancer (7.5-25% depending on series), but it increases significantly from well to poorly differentiated and undifferentiated carcinomas, up to 50% of all cases, indicating a strong association of these mutations with the aggressiveness and the metastatic spreading of thyroid malignancy (23,24,25,26,27,28).…”

Section: Introductionmentioning

confidence: 99%

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TERT promoter mutations are associated with distant metastases in papillary thyroid carcinoma

Gandolfi

Ragazzi

Frasoldati³

et al. 2015

European Journal of Endocrinology

107

121

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Objective: Transcriptional activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene were reported at high frequency in aggressive poorly differentiated and anaplastic thyroid cancers. By contrast, the relevance of these mutations in the metastatic behavior of well-differentiated thyroid cancer is still to be defined. The aim of this work was to investigate the frequency of TERT promoter mutations in a remarkable cohort of well-differentiated papillary thyroid carcinoma that developed distant metastases (DM-PTCs) and to establish whether these mutations may be predictive of metastatic behavior. Design: We analyzed the frequency of TERT promoter mutations in a group of 43 highly aggressive DM-PTCs. As controls, we analyzed these mutations in a group of 78 PTCs without distant metastases (control-PTCs). The possible correlation between TERT promoter mutations and BRAF V600E mutation was also investigated. Methods: TERT promoter mutational status was evaluated by direct sequencing of the hotspot harboring the C228T and the C250T mutations. Results: In the overall cohort of 121 PTCs analyzed, 17% of cases (21/121) carried a mutation in the TERT promoter. Noticeably, 33% of DM-PTCs were mutated in the TERT promoter while only 9% of the control-PTCs showed a mutation in this locus. We also observed a positive association between BRAF V600E and TERT C228T mutations in the cohort of DM-PTCs. Conclusions: These results indicate that TERT promoter mutations are associated with the development of distant metastases in PTCs and may help in predicting aggressive behavior in this type of tumor.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

TERT promoter mutations are associated with distant metastases in papillary thyroid carcinoma

Gandolfi

Ragazzi

Frasoldati³

et al. 2015

European Journal of Endocrinology

107

121

View full text Add to dashboard Cite

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“…Our results in TERT mRNA expression corroborated this assumption, showing an increased TERT expression in tumours harbouring BRAF and TERT mutation (48). Because BRAF has also been associated with worse prognosis in some studies, several authors hypothesized that both mutations could cooperate toward a worse prognosis (50,61). One still ignores the mechanism behind the putative cooperation between BRAF and TERT promoter mutation.…”

Section: Tert Promoter Mutationssupporting

confidence: 86%

ENDOCRINE TUMOURS: Genetic predictors of thyroid cancer outcome

Tavares

Melo

Cameselle-Teijeiro³

et al. 2016

European Journal of Endocrinology

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Genetic predictors of outcome are reviewed in the context of a disease -cancer -that can be (too) simplistically described as a 'successful, invasive clone of our own tissues'. Context has many faces that determine a thyroid cancer patient's outcome beyond the influence of genetic markers. There is also plenty of evidence on the prognostic meaning of the interplay between genetics and context/microenvironment factors (encapsulation, degree of invasion, staging, etc.). This review addresses only genetic alterations detected by molecular methods in surgically resected specimens, thus ruling out immunohistochemistry and (F)ISH, despite their crucial relevance as topographically oriented methods. For the sake of the discussion, well-differentiated carcinomas were divided into two main morphologic types: papillary carcinoma (classic and most variants) displaying BRAFV600E mutations and RET/papillary thyroid carcinoma rearrangements and the group of follicular patterned carcinomas that encompasses follicular carcinoma and the encapsulated form of follicular variant of papillary carcinoma, displaying RAS mutations and PAX8/PPARg rearrangement. TERT promoter mutations have been recently described (and associated with distant metastases and reduced survival) in papillary and follicular carcinomas, as well as in poorly differentiated and undifferentiated carcinoma. TP53 mutations, previously thought to be restricted to less differentiated carcinomas, were also detected in papillary and follicular carcinoma and found to carry a guarded prognosis. Besides their putative importance for targeted therapies, the prognostic meaning of such mutations is discussed per se and in the setting of concurrent BRAF mutation.

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“…Soon afterward, various studies demonstrated a consistent association between TERT mutation and poor clinicopathologic characteristics such as older age, the male sex, larger tumor size, extrathyroidal invasion, vascular invasion, distant metastasis, American Joint Committee on Cancer stage III or IV, recurrence, and death from follicular cellderived thyroid cancer (12)(13)(14)(15)(16). The poor prognosis of distant metastatic DTC is closely related to non-radioiodine avidity in distant metastatic lesions and eventually induces radioiodine-refractory status, thus posing a particularly tough prognostic and therapeutic challenge.…”

Section: Discussionmentioning

confidence: 99%

TERT Promoter Mutation Predicts Radioiodine-Refractory Character in Distant Metastatic Differentiated Thyroid Cancer

Yang

et al. 2016

J Nucl Med

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Telomerase reverse transcriptase (TERT) promoter mutation has been reported to be associated with aggressive characteristics in differentiated thyroid cancer (DTC). This study examined the status of TERT mutation in distant metastatic DTC and evaluated the correlation between TERT mutation and radioiodine uptake, as well as that between TERT mutation and therapy response. Methods: TERT promoter and B-Raf proto-oncogene (BRAF) V600E mutation were retrospectively examined in primary tumors of 66 patients with distant metastatic DTC. Stimulated thyroglobulin (sTg) changes, radioiodine uptake status (avid or nonavid), and other imaging evidence were analyzed to evaluate therapy response. After a median follow-up of 46.5 mo (interquartile range, 29.0-70.5 mo), therapy response was classified as either disease control or refractory. Results: The prevalence of TERT mutations was 22.73% (15/66), of which C228T mutation was more prevalent (13/15) than C250T mutation (2/15). Rising sTg was noticed in 93.33% (14/15) of the TERT mutation group. Of cases negative for both mutations, 78.12% (25/ 32) presented with decreased sTg. TERT mutation closely correlated with a poor response to radioiodine therapy (P , 0.001), and all 15 patients were classified as refractory to radioiodine therapy, with a positive predictive value of 100% at the endpoint of follow-up. TERT mutation was associated with older mean age at diagnosis (P , 0.001), larger mean tumor diameter (P 5 0.013), and greater likelihood of both BRAF mutation coexistence (P 5 0.044) and radioiodine-refractory character (P , 0.001). In the 36 cases whose imaging results underwent semiquantitative analysis, TERT mutation significantly correlated with non-radioiodine avidity, with a much lower mean tumor-to-background ratio (obtained from postradioiodine whole-body scanning) than in TERT wild-type cases (P , 0.001). In addition, patients with distant metastatic DTC with TERT mutation were more likely to lose radioiodine avidity at the initial radioiodine therapy than were those with only BRAF mutation (8/8 vs. 5/11; Fisher exact test, P 5 0.018). Conclusion: TERT mutation closely associates with non-radioiodine avidity in distant metastatic DTC, and when compared with BRAF mutation, TERT mutation manifested a greater negative influence on radioiodine uptake. TERT mutation could also be used as an early predictor of radioiodine-refractory cases.

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TERTPromoter Mutations and Their Association withBRAFV600E Mutation and Aggressive Clinicopathological Characteristics of Thyroid Cancer

Abstract: In this large cohort, we found TERT promoter mutations to be common, particularly in FTC and BRAF mutation-positive PTC, and associated with aggressive clinicopathological characteristics.

Cited by 261 publications

References 22 publications

TERT promoter mutations are associated with distant metastases in papillary thyroid carcinoma

TERT promoter mutations are associated with distant metastases in papillary thyroid carcinoma

ENDOCRINE TUMOURS: Genetic predictors of thyroid cancer outcome

TERT Promoter Mutation Predicts Radioiodine-Refractory Character in Distant Metastatic Differentiated Thyroid Cancer

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