Telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, plays a crucial role in maintaining telomere length. Telomerase, an RNA-dependent DNA polymerase, is involved in a pathway that ensures genome integrity by countering the gradual shortening of telomeres during DNA replication in successive mitoses. TERT is essential for cells to overcome cellular senescence induced by telomere shortening, and its regulation is key in normal cell differentiation and cancer development [1,2,4,5].

TERT activation is a fundamental step in tumorigenesis. TERT promoter mutations, which are highly recurrent and found in over 50 cancer types, upregulate TERT transcription. This activation via promoter mutation or other mechanisms is the rate-limiting step in producing active telomerase. In differentiated thyroid carcinoma, TERT-p mutations are associated with high-risk clinicopathological features and worse prognosis. In CNS tumors like meningiomas, medulloblastomas, and primary glial neoplasms, TERT promoter mutations lead to upregulated TERT transcription. Also, in urothelial carcinomas, TERT promoter mutations and aberrant methylation play important roles in TERT transcription activation and telomerase activation, with potential for non-invasive diagnostics and outcome prediction [2,3,4,6].

In conclusion, TERT is essential for telomere maintenance, a process crucial for cell immortality. Its dysregulation, especially through promoter mutations, is closely associated with cancer development in various tissues. The study of TERT in cancer, including through genetic models in vivo, has provided insights into tumorigenesis mechanisms, with potential implications for cancer diagnosis, prognosis, and the development of targeted therapies [1-3,5,6].

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/