Understanding TERT Promoter Mutations: A Common Path to Immortality

Abstract

Telomerase (TERT) activation is fundamental step in tumorigenesis. By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven by oncogenes. The recently discovered, highly recurrent mutations in the promoter of TERT are found in over 50 cancer types, and are the most common mutation in many cancers. Transcriptional activation of TERT, via promoter mutation or other mechanisms, is the rate-limiting step in production of active telomerase. While TERT is expressed in stem cells, it is naturally silenced upon differentiation. Thus, the presence of TERT promoter mutations may shed light on whether a particular tumor arose from a stem cell or more differentiated cell type. It is becoming clear that TERT mutations occur early during cellular transformation, and activate the TERT promoter by recruiting transcription factors that do not normally regulate TERT gene expression. This review highlights the fundamental and widespread role of TERT promoter mutations in tumorigenesis, including recent progress on their mechanism of transcriptional activation. These somatic promoter mutations, along with germline variation in the TERT locus also appear to have significant value as biomarkers of patient outcome. Understanding the precise molecular mechanism of TERT activation by promoter mutation and germline variation may inspire novel cancer cell-specific targeted therapies for a large number of cancer patients.

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

“…For example, although Simon and colleagues found no differences in frequency of MGMT methylation between pTERT mutant and wild-type tumors, the researchers did not differentiate between C228T and C250T mutations (9). This is perhaps reasonable as both hotspot mutations are known to generate an identical Ets/TCF transcription factorbinding motif (37)(38)(39). Very recently, however, functional differences between the C228T and C250T mutations with respect to NF-kB pathway activation has been reported (40).…”

Long-Range Chromatin Interactions Drive Mutant TERT Promoter Activation

“…Moreover, the TERT expression in these cells was comparable to that found in cancer cells and could signifi cantly delay telomere shortening-induced senescence. Furthermore, the high frequency of mutations in the TERT promoter mostly at two nucleotide positions (-146C>T, Long-distance elements -124C>T) strongly implicates them as driver events, appearing upon tumor initiation or possibly later in tumor development ( 27,28 ).…”

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

“…[45][46][47][48][49][50] More than 50 tumor types have now been shown to bear these hotspot mutations, and they often occur as an early driving step in tumorigenesis. 51 hTERT promoter mutations may additionally bear value as prognostic and diagnostic biomarkers insofar as they have been shown to be associated with decreased overall survival and aggressive histotypes in many cancers. 51 Through a G-to-A mutation (G/A) in the antisense strand, hTERT promoter mutations are proposed to generate an ETS/TCF element (CCGGAA) that would increase binding of the ETS transcription factor for activation of hTERT transcription.…”

“…51 hTERT promoter mutations may additionally bear value as prognostic and diagnostic biomarkers insofar as they have been shown to be associated with decreased overall survival and aggressive histotypes in many cancers. 51 Through a G-to-A mutation (G/A) in the antisense strand, hTERT promoter mutations are proposed to generate an ETS/TCF element (CCGGAA) that would increase binding of the ETS transcription factor for activation of hTERT transcription. 45,46 In addition, it has recently been suggested that the mutations found in glioblastoma multiforme could lead to recruitment of multimeric GA-binding protein (GABP) transcription factors to activate hTERT.…”