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

Abstract

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Tumor recurrence occurs in ∼20% of PTCs and some reach advanced stages. Promoter mutation in the telomerase reverse transcriptase (TERT) gene is identified to be a prognostic marker in PTC. However, the contribution of TERT promoter mutation to cancer progression in PTC patients is still not fully understood. In this study, we investigated the incidence of TERT promoter mutations and TERT protein expression and their association with clinicopathological outcomes in a large cohort of PTC samples using direct sequencing technology and immunohistochemistry. Furthermore, two PTC cell lines were utilized to investigate role of TERT mutations in mediating metastasis. Two promoter hotspot mutations C228T and C250T were identified in 18.0% (167/927) of our cohort and were significantly associated with poor 5 years disease-free survival and distant metastasis of PTC. TERT protein overexpression was noted in 20.1% of our PTC cohort and was significantly associated with poor prognostic markers such as older age, extrathyroidal extension and Stage IV tumors. A significant association was also found between TERT overexpression and epithelial-mesenchymal transition (EMT) markers. Functional analysis showed that TERT inhibition reduced cell growth, invasion, migration and angiogenesis in PTC via suppression of EMT in PTC cells. Our results suggest that TERT promoter mutation is an independent predictor of disease-free survival and might drive the metastasis, and downregulation of TERT could potentiate antitumor and antimetastatic activities in PTC.

Association between TERT promoter mutations and clinical behaviors in differentiated thyroid carcinoma: a systematic review and meta-analysis

“…Among 51 studies of overall DTC, 39 [11,[14][15][16][17][18][19][20], 26 [11, 14-17, 19, 20, 26-28, 32, 35, 36, 38-41, 44, 45, 47, 48, 51, 53, 54, 56, 57], 19 [11, 14-16, 19, 20, 27, 32, 35, 36, 44, 45, 47, 48, 53, 54, 56-58], 20 [17, 19, 20, 27, 30, 31, 34-37, 40, 42, 46-48, 51, 54, 55, 59, 60], 11 [16,17,20,28,31,37,44,50,55,57,60] [16-18, 20, 27, 28, 30, 31, 33, 35-38, 42, 43, 46, 56, 58, 60, 62, 64-67], and 14 [14,16,18,20,26,28,29,39,42,46,47,60,66,68] studies were analyzed for the associations between TERT promoter mutation and gender, mean age, mean tumor size, multifocality, vascular invasion, extrathyroidal extension, LNM, distant metastasis, advanced TNM stage, persistence/recurrence, and diseasespecific mortality, respectively. Among 41 studies of PTC, 32 [11, 14-19, 27-31, 33, 35-40, 42, 43, 45-47, 49-56], 19 [11, 14-17, 19, 27, 28, 35, 36, 38-40, 45 [17, 18, 27, 28, 30, 31, 33, 35-37, 39, 42, 43, 46, 56, 58, 62, 64, 66], and 10 [14,16,…”

“…, 47, 51, 53, 54, 56], 14[11, 14-16, 19, 27, 35, 36, 45, 47, 53, 54, 56, 58], 16 [17, 19, 27, 30, 31, 35-37, 40, 42, 46, 47, 51, 54, 55, 59], 7 [16, 17, 28, 31, 37, 50, 55], 23 [14-17, 19, 27, 30, 31, 35-38, 42, 43, 45, 46, 49-52, 54, 58, 61], 32[11, 14-19, 27-31, 33, 35, 37, 38, 40, 43, 45, 46, 49-56, 58, 59, 61, 62], 15[16,17,28,29,31,32,38,39,43,45,46,50,56,62,63], 24[15- 19, 27-31, 35-40, 42, 43, 45, 46, 50, 51, 54, 56],19 …”

Whole-Exome Sequencing of Matched Primary and Metastatic Papillary Thyroid Cancer

“…Therefore, our study focused on analyzing biopsies of primary PTC and distant metastases to compare the array of somatic mutations. Previously, TERT promoter mutations, in isolation and/or in combination with other driver mutations such as BRAF V600E , have been shown to play an important role in the development of a more aggressive phenotype and the development of metastases (46)(47)(48). The limitation of our exome sequencing approach limits the analyses to exonic mutations, not covering intronic or other regions.…”

<p>Downregulation of CDH16 in Papillary Thyroid Cancer and Its Potential Molecular Mechanism Analysed by qRT-PCR, TCGA and in silico Analysis</p>

“…6 Lymph node metastasis (LNM) is a potential factor that can aggravate the risk of locoregional recurrence and mortality in patients with PTC. [7][8][9][10] Recent studies revealed that several molecular biomarkers, such as BRAF 11,12 TERT, [13][14][15] PIK3CA 16,17 can facilitate LNM to some extent. Despite the in-depth research and progress on PTC studies, comprehensive clinical evaluation and molecular mechanistic exploration remain lacking.…”