Clinical utility of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of the BRAF V600E mutation

Abstract

BackgroundMutations in the TERT promoter, ALK rearrangement, and the BRAF V600E mutation are associated with aggressive clinicopathologic features in thyroid cancers. However, little is known about the impact of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of BRAF mutations.MethodsWe performed Sanger sequencing to detect BRAF V600E and TERT promoter mutations and both immunohistochemistry and fluorescence in situ hybridization to identify ALK rearrangement on 243 thyroid cancers.ResultsTERT promoter mutations were not present in 192 well-differentiated thyroid carcinomas (WDTC) without distant metastasis or in 9 medullary carcinomas. However, the mutations did occur in 40 % (12/30) of WDTC with distant metastasis, 29 % (2/7) of poorly differentiated carcinomas and 60 % (3/5) of anaplastic carcinomas. ALK rearrangement was not present in all thyroid cancers. The BRAF V600E mutation was more frequently found in WDTC without distant metastasis than in WDTC with distant metastasis (p = 0.007). In the cohort of WDTC with distant metastasis, patients with wild-type BRAF and TERT promoter had a significantly higher response rate after radioiodine therapy (p = 0.024), whereas the BRAF V600E mutation was significantly correlated with progressive disease (p = 0.025).ConclusionsThe TERT promoter mutation is an independent predictor for distant metastasis of WDTC, but ALK testing is not useful for clinical decision-making in Korean patients with a high prevalence of the BRAF V600E mutation. Radioiodine therapy for distant metastasis of WDTC is most effective in patients without BRAF V600E and TERT promoter mutations.

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

“…Consistent with previous studies, the present study on Chinese patients found a TERT mutation prevalence of 22.73% (15/66) in patients with distant metastatic DTC, with C250T mutation also being less frequent (2/15, 13.33%). In contrast, the incidence of TERT mutation in patients with distant metastatic DTC is slightly more common in South Korea (12/30, 40%) and Italy (14/43, 33%) (15,25). Our data also showed that besides being associated with radioiodine refractory status, TERT mutation in patients with distant metastatic DTC was associated with larger tumor size, older age, and greater likelihood of BRAF mutation coexistence, in agreement with previously published data (15).…”

Clinicopathological characteristics including BRAF V600E mutation status and PET/CT findings in papillary thyroid carcinoma

“…In contrast, research in Western countries has shown lower frequencies of the BRAF V600E mutation in patients with PTC . This may be associated with different genetic backgrounds, possibly related to molecular genotypes for the other oncogenic mutations, although this remains unclear …”

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.…”

“…Furthermore, the coexistence of BRAF V600E and TERT promoter mutations indicated more aggressive tumor and worse prognosis, and the influence of TERT promoter mutations seemed to be more significant than BRAF V600E mutation. 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.…”

“…Therefore, TERT promoter mutations can distinguish not only malignancy but also aggressive cases that need more positive therapeutic approach and vigilant monitoring. Some researchers also reported that patients with TERT promoter mutations tended to suffer from radiotherapeutic resistance;39,52 so TERT promoter mutations might also be potential predictors for therapeutic efficiency.…”