Thyroid carcinoma‐featured telomerase activation and telomere maintenance: Biology and translational/clinical significance

Abstract

Background Telomerase is a ribonucleoprotein complex consisting of a catalytic component telomerase reverse transcriptase (TERT), internal RNA template and other co‐factors, and its essential function is to synthesize telomeric DNA, repetitive TTAGGG sequences at the termini of linear chromosomes. Telomerase is silent in normal human follicular thyroid cells, primarily due to the TERT gene being tightly repressed. During the development and progression of thyroid carcinomas (TCs), TERT induction and telomerase activation is in general required to maintain telomere length, thereby conferring TC cells with immortal and aggressive phenotypes. Methods The genomic alterations of the TERT loci including TERT promoter's gain‐of‐function mutations, copy number gain, fusion and rearrangements, have recently been identified in TCs as mechanisms to induce TERT expression and to activate telomerase. Importantly, numerous studies have consistently shown that TERT promoter mutations and TERT expression occur in all TC subtypes, and are robustly associated with TC malignancy, aggressiveness, treatment failure and poor outcomes. Therefore, the assessment of TERT promoter mutations and TERT expression is highly valuable in TC diagnostics, prognosis, treatment decision, and follow‐up design. In addition, the TERT promoter is frequently hypermethylated in TC cells and tumors, which is required to activate TERT transcription and telomerase. Dysregulation of other components in the telomerase complex similarly upregulate telomerase. Moreover, shortened telomeres lead to altered gene expression and metabolism, thereby actively promoting TC aggressiveness. Here we summarize recent findings in TCs to provide the landscape of TC‐featured telomere/telomerase biology and discuss underlying implications in TC precision medicine. Conclusion Mechanistic insights into telomerase activation and TERT induction in TCs are important both biologically and clinically. The TERT gene aberration and expression‐based molecular classification of TCs is proposed, and for such a purpose, the standardization of the assay and evaluation system is required. Moreover, the TERT‐based system and 2022 WHO TC classification may be combined to improve TC care.

TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance

“…Similar findings were reported by others ( 70 ). These results suggest that the TERT promoter is targeted for mutation at an early stage of carcinogenesis, and even in benign tumors lacking malignant characteristics at pathological and morphological levels ( 63 ). The early onset of TERT promoter mutations is highly consistent with recent observations that oncogenic genomic alterations may take place in childhood or adolescent periods long before cancer formation ( 71 ).…”

“…Indeed, following stable GABPB1 knockdown, glioblastoma cells carrying C228T or C250T TERT promoters undergo diminished TERT/telomerase expression, progressive telomere erosion and eventual loss of tumorigenic potential ( 55 ). However, GABPA and GABPB1 stimulate TERT transcription, but several lines of evidence suggest that they may serve as tumor suppressors in other cancer types regardless the presence or absence of TERT promoter mutations ( 56 , 58 – 63 ). In UCBs, TCs and renal cell carcinomas (RCCs), GABPA or GABPB1 inhibition promotes their stemness and invasiveness, despite downregulation of TERT expression ( 59 , 60 , 63 ).…”

“…However, GABPA and GABPB1 stimulate TERT transcription, but several lines of evidence suggest that they may serve as tumor suppressors in other cancer types regardless the presence or absence of TERT promoter mutations ( 56 , 58 – 63 ). In UCBs, TCs and renal cell carcinomas (RCCs), GABPA or GABPB1 inhibition promotes their stemness and invasiveness, despite downregulation of TERT expression ( 59 , 60 , 63 ). Moreover, GABPA-depleted UCB cells resisted cisplatin-induced apoptosis ( 59 ).…”

“…Mechanistically, GABPA activates the transcription of its target genes Fox-A1 and GATA3, two important differentiation-promoters of urothelial cells, while insufficiency or deficiency of GABPA expression results in blockade of cellular differentiation, thereby inducing an immature UCB status characterized by enriched stemness and EMT phenotypes ( 59 ). In primary tumors derived from patients with UCB, TC and RCC, GABPA expression is inversely correlated with advanced stage, aggressive or metastatic diseases and survival ( 59 , 63 ). Intriguingly, GABPA and TERT expression even anti-correlated with each other in these tumors, suggesting a more complicated in vivo relationship between them ( 59 ).…”

“…It is known that old individuals have shorter telomeres in their tissues/cells, and telomere dysfunction occurs earlier during the oncogenic process, which thus experiences strong pressure for telomere stabilization. Third, the presence of TERT promoter mutations are strongly correlated with activating mutations in mitogen-activated protein kinase (MAPK) genes, such as FGFR3 , BRAF , and RAS in UCBs, melanoma and TCs, respectively ( 43 , 63 , 65 , 67 ). The MAPK hyperactivity accelerates cell proliferation, inducing excessive telomere attrition and dysfunction.…”