The Solo Play of TERT Promoter Mutations

Abstract

The reactivation of telomerase reverse transcriptase (TERT) protein is the principal mechanism of telomere maintenance in cancer cells. Mutations in the TERT promoter (TERTp) are a common mechanism of TERT reactivation in many solid cancers, particularly those originating from slow-replicating tissues. They are associated with increased TERT levels, telomere stabilization, and cell immortalization and proliferation. Much effort has been invested in recent years in characterizing their prevalence in different cancers and their potential as biomarkers for tumor stratification, as well as assessing their molecular mechanism of action, but much remains to be understood. Notably, they appear late in cell transformation and are mutually exclusive with each other as well as with other telomere maintenance mechanisms, indicative of overlapping selective advantages and of a strict regulation of TERT expression levels. In this review, we summarized the latest literature on the role and prevalence of TERTp mutations across different cancer types, highlighting their biased distribution. We then discussed the need to maintain TERT levels at sufficient levels to immortalize cells and promote proliferation while remaining within cell sustainability levels. A better understanding of TERT regulation is crucial when considering its use as a possible target in antitumor strategies.Cells 2020, 9, 749 2 of 28 by copy number variants (CNV), TERT or TERTp structural variants, chromosomal rearrangements juxtaposing TERTp to enhancer elements, cellular and viral oncogenes such as Hepatitis B virus (HBV) X protein (HBx) or high-risk Human papillomavirus (HPV)16 and HPV18 E6 oncoprotein, and, last but not least, mutations within TERTp (31% of TERT-expressing cancers) ( Figure 1A) [10, 30-38] (reviewed in [3,4,9,18-20,39]). Increased TERTp methylation is typically recorded in >50% of TERT-expressing tumors and cell lines [10,[40][41][42][43][44][45][46][47]. Epigenetic regulation of TERTp is based on altered methylation patterns of specific regions. Hypomethylation of the region between −200 and −100 from the Translational Start site (TSS), encompassing the core promoter, enables binding of c-Myc and Sp-1, thus reactivating transcription. In contrast, the region spanning exon 1 (positions +1 to ±100 from the TSS) contains a binding site for the DNA insulator CTCF. Hypermethylation of this region disrupts binding of CTCF and therefore allows TERT transcription [41][42][43][44]. Similarly, the region between −600 and −200 from the TSS contains a second CTCF binding site and is partially hypermethylated in TERT-expressing cells [41][42][43][44].

Molecular Features of Metaplastic Breast Carcinoma: An Infrequent Subtype of Triple Negative Breast Carcinoma

“…In this sense, some series have demonstrated gene mutations that modulate the WNT pathway, such as APC (5%), a key component of the beta-catenin degradation complex, and FAT1 (11%) ( Table S1 ). Moreover, it is well established that TERT promoter mutations can activate the WNT pathway, among others, through telomere-independent mechanisms [ 42 ].…”

Anti-Cancer Immunotherapies Targeting Telomerase

“…The crucial role of telomerase in tumor growth and development suggests that hTERT down-modulation as a means of immune escape may itself have deleterious effects on cancer cells. Recently, comprehensive whole-genome analysis has identified that the accumulation of point mutations within the promoter region of the hTERT gene is responsible for the increased TERT expression [13]. Only in a minority of cancer, telomere length maintenance is achieved by telomerase-independent mechanisms, referred to as "alternative lengthening of telomeres" (ALT) [14].…”

TERT promoter alterations could provide a solution for Peto’s paradox in rodents

“…Telomerase is a multi-subunit complex; its activity in different placental mammals is determined primarily by the transcription of its catalytic subunit (TERT) 31,56,57 . TERT regulation is quite complex including regulation by transcription factors like the Myc/Max/Mad protein family and many others ( Supplementary Fig S4.), miR-NAs, alternative splicing, post translational modifications and subcellular trafficking-for reviews see 29,[57][58][59][60][61] . The lengths of telomeres in studied species correlate with telomerase expression levels 22 , and several experiments have www.nature.com/scientificreports/ demonstrated that telomere shortening happens due to the deletion or down-regulation of TERT 24,27 .…”

“…Telomerase activation is responsible for the immortalization of approximately 90% of tumor cells. The activation could happen in multiple ways, such as through epigenetic changes, alternative splicing, or by the previously mentioned TERT promoter mutation—for reviews see 31 , 61 . In tumors the change in the − 124 or − 146 bp position in the promoter regions creates ETS factor recognition motifs.…”