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

Abstract

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.

TERT promoter mutations in thyroid cancer: a report from a Middle Eastern population

“…Similar to previous studies, ours showed TERT promoter mutations in 8/57 (14%) cases of FVPTC. This is similar to the rate reported in a large series of TC in which 18 out of 103 cases (14.6%) of FVPTC harbored TERT promoter mutations ) and another smaller study from Europe showing a similar rate (Gandolfi et al 2015).…”

“…In our study, the prevalence of TERT promoter mutations in CPTC was relatively low (6.5%). Other studies showed rates that ranged between 4.5 and 22.5%, with most studies showing a frequency of TERT promoter mutations of around 12% in CPTC (Landa et al 2013, Liu et al 2013, Vinagre et al 2013, Gandolfi et al 2015, Muzza et al 2015. Similar to previous studies, ours showed TERT promoter mutations in 8/57 (14%) cases of FVPTC.…”

“…Studies from these regions have shown that TERT promoter mutations are associated with more aggressive histopathological features and worse outcomes (Landa et al 2013, Liu et al 2013,b, Vinagre et al 2013, Ngeow & Eng 2014, Gandolfi et al 2015, Shi et al 2015. Similar and consistent findings from other ethnic groups would support these conclusions and firmly establish the association between TERT promoter mutations and the risk of aggressiveness of DTC.…”

“…The contribution of genetic mutations in the MAPK and phosphatidylinositide 3-kinases (PI3KCa)-AKT pathways in the pathogenesis of DTC are well established, and new pathways and genes are being discovered as additional drivers for the initiation and progression of DTC (Agrawal et al 2014). These new genetic aberrations include mutations in the telomerase reverse transcriptase (TERT) promoter (Landa et al 2013, Liu et al 2013, Vinagre et al 2013, Ngeow & Eng 2014, Gandolfi et al 2015. TERT is the catalytic subunit of telomerase which is composed of a ribonucleoprotein complex that is responsible for adding telomeric fragments to chromosomes, maintaining the telomere length that usually shortens over time in the dividing somatic cells (Smekalova et al 2012).…”

“…Although mutations in the coding regions of the TERT gene are rare, TERT promoter mutations (C288T and C250T) have recently been described in many types of human cancers, including the follicular cell-derived TC (Landa et al 2013, Liu et al 2013, Vinagre et al 2013. They were also found to be associated with more aggressive tumors and with high rate of BRAF V600E mutation (Landa et al 2013, Liu et al 2013,b, Liu & Xing 2014, Gandolfi et al 2015, Shi et al 2015. These studies have been mostly conducted in North American and European populations.…”