Mechanisms of TERT Reactivation and Its Interaction with BRAFV600E

Abstract

The telomerase reverse transcriptase (TERT) gene, which is repressed in most differentiated human cells, can be reactivated by somatic TERT alterations and epigenetic modulations. Moreover, the recruitment, accessibility, and binding of transcription factors also affect the regulation of TERT expression. Reactivated TERT contributes to the development and progression of cancer through telomere lengthening-dependent and independent ways. In particular, because of recent advances in high-throughput sequencing technologies, studies on genomic alterations in various cancers that cause increased TERT transcriptional activity have been actively conducted. TERT reactivation has been reported to be associated with poor prognosis in several cancers, and TERT promoter mutations are among the most potent prognostic markers in thyroid cancer. In particular, when a TERT promoter mutation coexists with the BRAF V600E mutation, these mutations exert synergistic effects on a poor prognosis. Efforts have been made to uncover the mechanisms of these synergistic interactions. In this review, we discuss the role of TERT reactivation in tumorigenesis, the mechanisms of TERT reactivation across all human cancers and in thyroid cancer, and the mechanisms of interactions between BRAF V600E and TERT promoter mutations.

Prospective Analysis of TERT Promoter Mutations in Papillary Thyroid Carcinoma at a Single Institution

“…Overexpression of the TERT gene then increases tumor cell telomere stability and is linked to cell overdevelopment and malignant transformation. These molecular consequences contribute to cancer cell immortality, which is thought to be associated with the aggressive behavior and poor survival of PTC [ 20 , 21 ].…”

How limited molecular testing can also offer diagnostic and prognostic evaluation of thyroid nodules processed with liquid‐based cytology: Role of TERT promoter and BRAF V600E mutation analysis

“…49,50 Other studies have reported a correlation between BRAF V600E and more aggressive clinicopathologic outcomes of cPTC, especially with respect to bilateral disease, extrathyroidal extension, and nodal involvement. [5][6][7][8][9][10][11][12][13][14][15] Although data from the current series confirm the correlation of BRAF V600E with nodal involvement (P = .0349), no correlation was noted with disease multifocality. 42 Similar findings were documented by Ahmad et al, who concluded that the association of BRAF V600E mutation with extrathyroidal extension indicates its aggressive nature and thus can provide insights into the potential progression of thyroid tumors.…”

“…Specifically, it was the last decade in which researchers emphasized the role in thyroid cancer oncogenesis played by activation of the MAPK and PI3K-AKT signaling pathways, [5][6][7][8][9][10][11] with the BRAF V600E mutation frequently found in PTCs and involved in neoplasia initiation and progression to de-differentiation. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Several authors confirmed that the sensitivity of molecular testing was improved through the introduction of gene panels and next-generation sequencing (NGS), which can detect multiple types of genetic alterations in 1 assay using a very small number of cells obtained from thyroid FNA samples. The benefits are mostly linked to the finding that NGS has high sensitivity and is able to quantitatively assess the proportion of cells carrying a given mutation.…”

“…20 Additional events, such as TP53 and TERT promoter mutations, occur late in oncogenesis with increasing frequency in thyroid cancers that lose differentiation and are associated with an unfavorable outcome and prognosis. [12][13][14][15][16][17][18][19][20][21][22] In fact, the TERT gene, which is repressed in most differentiated human cells, can be reactivated by somatic TERT alterations, which is also induced by transcription factors. Specifically, reactivated TERT contributes to the development and progression of cancer and to a poor prognosis in several cancers.…”

“…Specifically, reactivated TERT contributes to the development and progression of cancer and to a poor prognosis in several cancers. 14 Some authors have documented that TERT promoter mutations are commonly found in poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma (eg, in up to 70% of cases), although such TERT mutations (namely, C228T and C250T) have also been identified in PTC and its variants as well as Hurtle cell carcinoma. 15,[23][24][25][26][27][28][29][30][31] Nevertheless, when a TERT promoter mutation coexists with a BRAF V600E mutation, thyroid cancers, including PTCs, are likely to have a synergic role in a poorer prognosis and a negative effect on clinical outcome.…”