TERT promoter mutations are a major indicator of recurrence and death due to papillary thyroid carcinomas

Abstract

SummaryContext TERT promoter mutations have been associated with adverse prognosis in papillary thyroid carcinomas (PTCs).ObjectiveWe investigated the association between TERT promoter mutations and survival from PTC.DesignRetrospective observational cohort study.PatientsEighty consecutive patients with PTC who underwent surgery between 1990 and 2003.Measurements TERT promoter was genotyped in DNA from 80 archival PTCs by Sanger sequencing. Median follow‐up was 106 months (range 1–270). Outcomes analysis was stratified according to disease and overall survival status. For each parameter, relative risk (RR) adjusted for age at first surgery and gender was estimated. Both univariate and multivariate analyses were performed using logistic regression, Kaplan–Meier survival analysis and Cox regression models.Results PTCs from 11 patients (14%) contained either C228T or C250T TERT promoter mutation. TERT mutations were significantly associated with adverse prognostic features such as older age (P = 0·002), male gender (P = 0·01) and Stage IV disease (P = 0·03). Four patients died from PTC during follow‐up: 3 patients with TERT mutations (27%) and one without (1·5%). Disease‐related mortality rate with or without TERT mutations was 33·7 vs 1·6 per 1000 patient‐years respectively, that is 10 (95% CI = 1·0–104·1, P = 0·05) fold higher, after adjustment for age at first surgery and gender. The combination of TERT promoter mutation and BRAFV 600E significantly increased disease‐related death risk (P = 0·002). TERT mutations increased expression of a reporter gene in thyroid cells containing BRAFV 600E.Conclusions TERT promoter mutations are a major indicator of death due to PTCs. Conversely, absence of TERT mutations portends better survival.

Telomerase reverse transcriptase mutations are independent predictor of disease‐free survival in Middle Eastern papillary thyroid cancer

“…Similarly, Bullock et al . found a poor disease‐free survival in TERT mutated cases in their cohort of 80 cases . However, another study by Qasem et al .…”

Association of telomerase reverse transcriptase promoter mutations with clinicopathological features and prognosis of thyroid cancer: a meta-analysis

“…Full-text of the remaining 40 studies were further evaluated, and 22 studies with 4,907 patients were ultimately included in this meta-analysis 12–17,22,23,27,30–42. All the 22 studies reported the frequency of TERT promoter mutations,12–17,22,23,27,30–42 18 studies were available for analyzing the clinicopathological features and prognostic significance,14–17,22,23,27,31–33,35–42 15 studies investigated the relationship of TERT promoter and BRAF V600E mutations,13,15,16,22,23,27,33–37,39–42 and six of them evaluated the synergetic effect of both mutations 15,24,25,35,37,41. According to the NOS system, 11 studies were classified as high-quality and the other 11 were mid-range.…”

“…The mechanism underlying the synergetic effect of BRAF and TERT promoter mutations remains uncertain 15,24,25,29,30,39,50. Vinagre et al and Bullock et al demonstrated that BRAF and TERT promoter mutations can increase the expression of each other,17,37 which may be achieved by activation of MAPK pathway and regulation of ETS transcriptional factors 50. Li et al found that C250T mutation alone was insufficient to drive the transcription of TERT gene and required noncanonical NF-κB signaling for stimulus responsiveness at the same time 51.…”

Young Investigator Challenge: Molecular testing in noninvasive follicular thyroid neoplasm with papillary‐like nuclear features

“…No such criteria were used in our case despite very thorough microscopic evaluation. Promoter mutations in thyroid cancer have been associated with worse outcomes, particularly when present in conjunction with a BRAF mutation in classical papillary thyroid carcinoma . Similarly, worse tumor behavior has been reported with concurrent RAS and TERT mutations in differentiated thyroid cancer .…”