Telomerase reverse transcriptase (TERT), also known as hTERT, is the catalytic subunit of telomerase. Telomerase, an RNA-dependent DNA polymerase, plays a key role in maintaining telomere length, which is crucial for cell replication. As cells divide, telomeres shorten, and telomerase, through TERT, counteracts this by adding telomeric repeats, thus enabling cells to overcome senescence. This process is integral to normal stem cell function and is also hijacked in cancer cells, allowing them to achieve limitless proliferation [1,2,4,5].

TERT activation is a fundamental step in tumorigenesis. TERT promoter mutations are highly recurrent in over 50 cancer types, and they upregulate TERT transcription [2]. In differentiated thyroid carcinoma, these mutations are associated with high-risk clinicopathological features and worse prognosis [3]. In CNS tumors, such as meningiomas, medulloblastomas, and primary glial neoplasms, TERT promoter mutations lead to upregulation of TERT transcription, while in ependymomas and pediatric brain tumors, TERT promoter hypermethylation has the same effect [4]. In urothelial carcinomas, TERT promoter mutations and aberrant methylation play important roles in TERT transcription activation and telomerase activation, which is essential for tumor development and progression [6].

In conclusion, TERT is essential for telomere maintenance, a process vital for normal stem cell function and one that is misregulated in cancer. The study of TERT, especially through understanding its promoter mutations and epigenetic modifications as seen in various cancer types, provides insights into cancer pathogenesis. This knowledge may help develop novel cancer therapies targeting TERT-related pathways, aiming to disrupt the abnormal telomere maintenance that drives cancer cell immortality.

References:

1. Dratwa, Marta, Wysoczańska, Barbara, Łacina, Piotr, Kubik, Tomasz, Bogunia-Kubik, Katarzyna. 2020. TERT-Regulation and Roles in Cancer Formation. In Frontiers in immunology, 11, 589929. doi:10.3389/fimmu.2020.589929. https://pubmed.ncbi.nlm.nih.gov/33329574/

2. Bell, Robert J A, Rube, H Tomas, Xavier-Magalhães, Ana, Song, Jun S, Costello, Joseph F. 2016. Understanding TERT Promoter Mutations: A Common Path to Immortality. In Molecular cancer research : MCR, 14, 315-23. doi:10.1158/1541-7786.MCR-16-0003. https://pubmed.ncbi.nlm.nih.gov/26941407/

3. Matsuse, Michiko, Mitsutake, Norisato. 2023. TERT promoter mutations in thyroid cancer. In Endocrine journal, 70, 1035-1049. doi:10.1507/endocrj.EJ23-0136. https://pubmed.ncbi.nlm.nih.gov/37532521/

4. Patel, Bhuvic, Taiwo, Rukayat, Kim, Albert H, Dunn, Gavin P. 2020. TERT, a promoter of CNS malignancies. In Neuro-oncology advances, 2, vdaa025. doi:10.1093/noajnl/vdaa025. https://pubmed.ncbi.nlm.nih.gov/32226942/

5. Heidenreich, Barbara, Kumar, Rajiv. 2016. TERT promoter mutations in telomere biology. In Mutation research. Reviews in mutation research, 771, 15-31. doi:10.1016/j.mrrev.2016.11.002. https://pubmed.ncbi.nlm.nih.gov/28342451/

6. Liu, Tiantian, Li, Shihong, Xia, Chuanyou, Xu, Dawei. 2023. TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance. In Frontiers in immunology, 13, 1071390. doi:10.3389/fimmu.2022.1071390. https://pubmed.ncbi.nlm.nih.gov/36713366/