Telomeres and telomerase in mesothelioma: Pathophysiology, biomarkers and emerging therapeutic strategies (Review).

Abstract

Malignant mesothelioma (MM) is a rare but aggressive cancer linked to asbestos exposure and characterized by advanced‑stage disease at presentation. Despite advances in treatment, prognosis remains abysmal, highlighting the imperative for the development of novel biomarkers and treatment approaches. Telomere biology plays a pivotal role in the tumorigenic process and has emerged as a key area in oncology research. Short telomeres have been associated with genomic instability, and substantially shorter telomere length (TL) has been identified in MM, showcasing the potential of TL in risk assessment, early detection, and disease progression monitoring. MM predominantly maintains TL through telomerase activity (TA), which in research has been identified in >90% of MM cases, underscoring the potential of TA as a biomarker in MM. Telomerase reverse transcriptase (TERT) polymorphisms may serve as valuable biomarkers, with research identifying associations between single nucleotide polymorphisms (SNPs) and the risk and prognosis of MM. Additionally, TERT promoter mutations have been associated with poor prognosis and advanced‑stage disease, with the non‑canonical functions of TERT hypothesized to contribute to the development of MM. TERT promoter mutations occur in ~12% of MM cases; C228T, C250T and A161C are the most common, while the distribution and frequency differ depending on histological subtype. Research reveals the promise of the various approaches therapeutically targeting telomerase, with favorable results in pre‑clinical models and inconclusive findings in clinical trials. The present review examines the role of telomere biology in MM and its implications in diagnosis, prognosis, and therapy.