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Telomerase reverse transcriptase promoter mutations in non-small cell lung cancer: Biology and clinical significance

Year 2025, Volume: 6 Issue: 1, 60 - 64, 30.04.2025

Onur Dülger

https://doi.org/10.51753/flsrt.1576211

Abstract

About 85% of all lung cancers are non-small cell lung cancers (NSCLC), which are common, have a high death rate, and are usually diagnosed at an advanced stage. Recent studies have shown that mutations in the TERT promoter in NSCLC may be a noninvasive biomarker, enhance possible treatment approaches, and predict prognosis, especially in inoperable cases. This review comprehensively examines the present state of TERT promoter mutations in NSCLC, highlighting their clinical relevance, treatment approaches, challenges, and key considerations. TERT promoter mutations in NSCLC may offer new perspectives on the molecular pathogenesis of patients. For this reason, summarized TERT promoter mutations in NSCLC and current treatment strategies targeting TERT. Understanding the TERT effect on NSCLC may pave the way for new personalized treatment approaches.

Keywords

Clinical significance non-small cell lung cancer promoter mutations TERT

References

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  • Alamgeer, M., Ganju, V., & Watkins, D. N. (2013). Novel therapeutic targets in non-small cell lung cancer. Current Opinion in Pharmacology, 13(3), 394-401.
  • Ali, J. H., & Walter, M. (2023). Combining old and new concepts in targeting telomerase for cancer therapy: transient, immediate, complete and combinatory attack (TICCA). Cancer Cell International, 23(1), 197.
  • Asangani, I. A., Dommeti, V. L., Wang, X., Malik, R., Cieslik, M., Yang, R., ... & Chinnaiyan, A. M. (2014). Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature, 510(7504), 278-282.
  • Aubert, G., Baerlocher, G. M., Vulto, I., Poon, S. S., & Lansdorp, P. M. (2012). Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes. PLoS Genetics, 8(5), e1002696.
  • Barthel, F. P., Wei, W., Tang, M., Martinez-Ledesma, E., Hu, X., Amin, S. B., ... & Verhaak, R. G. (2017). Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nature Genetics, 49(3), 349-357.
  • Bertolaccini, L., Casiraghi, M., Uslenghi, C., Maiorca, S., & Spaggiari, L. (2024). Recent advances in lung cancer research: unravelling the future of treatment. Updates in Surgery, 76(6), 2129-2140.
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  • Dosset, M., Castro, A., Carter, H., & Zanetti, M. (2020). Telomerase and CD4 T cell immunity in cancer. Cancers, 12(6), 1687.
  • El Zarif, T., Machaalani, M., Nawfal, R., Nassar, A. H., Xie, W., Choueiri, T. K., & Pomerantz, M. (2024). TERT promoter mutations frequency across race, sex, and cancer type. The Oncologist, 29(1), 8-14.
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  • Fois, S. S., Paliogiannis, P., Zinellu, A., Fois, A. G., Cossu, A., & Palmieri, G. (2021). Molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer. International Journal of Molecular Sciences, 22(2), 612.
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  • Griewank, K. G., Murali, R., Schilling, B., Schimming, T., Möller, I., Moll, I., ... & Hillen, U. (2013). TERT promoter mutations are frequent in cutaneous basal cell carcinoma and squamous cell carcinoma. PloS one, 8(11), e80354.
  • Guterres, A. N., & Villanueva, J. (2020). Targeting telomerase for cancer therapy. Oncogene, 39(36), 5811-5824.
  • Heidenreich, B., & Kumar, R. (2017). TERT promoter mutations in telomere biology. Mutation Research/Reviews in Mutation Research, 771, 15-31.
  • Hirsch, F. R., Wynes, M. W., Gandara, D. R., & Bunn Jr, P. A. (2010). The tissue is the issue: personalized medicine for non-small cell lung cancer. Clinical Cancer Research, 16(20), 4909-4911.
  • Horn, S., Figl, A., Rachakonda, P. S., Fischer, C., Sucker, A., Gast, A., ... & Kumar, R. (2013). TERT promoter mutations in familial and sporadic melanoma. Science, 339(6122), 959-961.
  • Hsu, C. P., Hsu, N. Y., Lee, L. W., & Ko, J. L. (2006). Ets2 binding site single nucleotide polymorphism at the hTERT gene promoter–effect on telomerase expression and telomere length maintenance in non-small cell lung cancer. European Journal of Cancer, 42(10), 1466-1474.
  • Huang, F. W., Hodis, E., Xu, M. J., Kryukov, G. V., Chin, L., & Garraway, L. A. (2013). Highly recurrent TERT promoter mutations in human melanoma. Science, 339(6122), 957-959.
  • Inada, E., Saitoh, I., Kubota, N., Iwase, Y., Kiyokawa, Y., Shibasaki, S., ... & Sato, M. (2019). piggy Bac transposon-based immortalization of human deciduous tooth dental pulp cells with multipotency and non-tumorigenic potential. International Journal of Molecular Sciences, 20(19), 4904.
  • Jafri, M. A., Ansari, S. A., Alqahtani, M. H., & Shay, J. W. (2016). Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine, 8(1), 69. https://doi.org/10.1186/s13073-016-0324-x
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Telomerase reverse transcriptase promoter mutations in non-small cell lung cancer: Biology and clinical significance

Year 2025, Volume: 6 Issue: 1, 60 - 64, 30.04.2025

Onur Dülger

https://doi.org/10.51753/flsrt.1576211

Abstract

About 85% of all lung cancers are non-small cell lung cancers (NSCLC), which are common, have a high death rate, and are usually diagnosed at an advanced stage. Recent studies have shown that mutations in the TERT promoter in NSCLC may be a noninvasive biomarker, enhance possible treatment approaches, and predict prognosis, especially in inoperable cases. This review comprehensively examines the present state of TERT promoter mutations in NSCLC, highlighting their clinical relevance, treatment approaches, challenges, and key considerations. TERT promoter mutations in NSCLC may offer new perspectives on the molecular pathogenesis of patients. For this reason, summarized TERT promoter mutations in NSCLC and current treatment strategies targeting TERT. Understanding the TERT effect on NSCLC may pave the way for new personalized treatment approaches.

Keywords

Clinical significance non-small cell lung cancer promoter mutations TERT

References

  • Akincilar, S. C., Unal, B., & Tergaonkar, V. (2016). Reactivation of telomerase in cancer. Cellular and Molecular Life Sciences, 73, 1659-1670.
  • Alamgeer, M., Ganju, V., & Watkins, D. N. (2013). Novel therapeutic targets in non-small cell lung cancer. Current Opinion in Pharmacology, 13(3), 394-401.
  • Ali, J. H., & Walter, M. (2023). Combining old and new concepts in targeting telomerase for cancer therapy: transient, immediate, complete and combinatory attack (TICCA). Cancer Cell International, 23(1), 197.
  • Asangani, I. A., Dommeti, V. L., Wang, X., Malik, R., Cieslik, M., Yang, R., ... & Chinnaiyan, A. M. (2014). Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature, 510(7504), 278-282.
  • Aubert, G., Baerlocher, G. M., Vulto, I., Poon, S. S., & Lansdorp, P. M. (2012). Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes. PLoS Genetics, 8(5), e1002696.
  • Barthel, F. P., Wei, W., Tang, M., Martinez-Ledesma, E., Hu, X., Amin, S. B., ... & Verhaak, R. G. (2017). Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nature Genetics, 49(3), 349-357.
  • Bertolaccini, L., Casiraghi, M., Uslenghi, C., Maiorca, S., & Spaggiari, L. (2024). Recent advances in lung cancer research: unravelling the future of treatment. Updates in Surgery, 76(6), 2129-2140.
  • Braicu, C., Zimta, A. A., Harangus, A., Iurca, I., Irimie, A., Coza, O., & Berindan-Neagoe, I. (2019). The function of non-coding RNAs in lung cancer tumorigenesis. Cancers, 11(5), 605.
  • Bremnes, R. M., Sundstrom, S., Aasebø, U., Kaasa, S., Hatlevoll, R., Aamdal, S., & Norwegian Lung Cancer Study Group. (2003). The value of prognostic factors in small cell lung cancer: results from a randomised multicenter study with minimum 5 year follow-up. Lung Cancer, 39(3), 303-313.
  • Brennan, C. W., Verhaak, R. G., McKenna, A., Campos, B., Noushmehr, H., Salama, S. R., ... & Davidsen, T. (2013). The somatic genomic landscape of glioblastoma. Cell, 155(2), 462-477.
  • Brundage, M. D., Davies, D., & Mackillop, W. J. (2002). Prognostic factors in non-small cell lung cancer: a decade of progress. Chest, 122(3), 1037-1057.
  • Campisi, J. (2013). Aging, cellular senescence, and cancer. Annual Review of Physiology, 75(1), 685-705.
  • Chen, Z., Vallega, K. A., Wang, D., Quan, Z., Fan, S., Wang, Q., ... & Sun, S. Y. (2024). Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer. Journal of Experimental Medicine, 221(11), e20240435.
  • Cheng, H., Xu, X., Costa, D. B., Powell, C. A., & Halmos, B. (2010). Molecular testing in lung cancer: the time is now. Current Oncology Reports, 12, 335-348.
  • Dacic, S. (2011). Molecular diagnostics of lung cancer. Archives of Pathology & Laboratory Medicine, 135, 623–829.
  • Dilley, R. L., & Greenberg, R. A. (2015). ALTernative telomere maintenance and cancer. Trends in Cancer, 1, 145-156.
  • Dosset, M., Castro, A., Carter, H., & Zanetti, M. (2020). Telomerase and CD4 T cell immunity in cancer. Cancers, 12(6), 1687.
  • El Zarif, T., Machaalani, M., Nawfal, R., Nassar, A. H., Xie, W., Choueiri, T. K., & Pomerantz, M. (2024). TERT promoter mutations frequency across race, sex, and cancer type. The Oncologist, 29(1), 8-14.
  • Fekri Aval, S., Akbarzadeh, A., Yamchi, M. R., Zarghami, F., Nejati-Koshki, K., & Zarghami, N. (2016). Gene silencing effect of SiRNA-magnetic modified with biodegradable copolymer nanoparticles on hTERT gene expression in lung cancer cell line. Artificial Cells, Nanomedicine, and Biotechnology, 44(1), 188-193.
  • Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., ... & Bradner, J. E. (2010). Selective inhibition of BET bromodomains. Nature, 468(7327), 1067-1073.
  • Fois, S. S., Paliogiannis, P., Zinellu, A., Fois, A. G., Cossu, A., & Palmieri, G. (2021). Molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer. International Journal of Molecular Sciences, 22(2), 612.
  • Gridelli, C., Ciuleanu, T., Domine, M., Szczesna, A., Bover, I., Cobo, M., ... & Vx-001-201 trial team. (2020). Clinical activity of a htert (vx-001) cancer vaccine as post-chemotherapy maintenance immunotherapy in patients with stage IV non-small cell lung cancer: final results of a randomised phase 2 clinical trial. British Journal of Cancer, 122(10), 1461-1466.
  • Griewank, K. G., Murali, R., Schilling, B., Schimming, T., Möller, I., Moll, I., ... & Hillen, U. (2013). TERT promoter mutations are frequent in cutaneous basal cell carcinoma and squamous cell carcinoma. PloS one, 8(11), e80354.
  • Guterres, A. N., & Villanueva, J. (2020). Targeting telomerase for cancer therapy. Oncogene, 39(36), 5811-5824.
  • Heidenreich, B., & Kumar, R. (2017). TERT promoter mutations in telomere biology. Mutation Research/Reviews in Mutation Research, 771, 15-31.
  • Hirsch, F. R., Wynes, M. W., Gandara, D. R., & Bunn Jr, P. A. (2010). The tissue is the issue: personalized medicine for non-small cell lung cancer. Clinical Cancer Research, 16(20), 4909-4911.
  • Horn, S., Figl, A., Rachakonda, P. S., Fischer, C., Sucker, A., Gast, A., ... & Kumar, R. (2013). TERT promoter mutations in familial and sporadic melanoma. Science, 339(6122), 959-961.
  • Hsu, C. P., Hsu, N. Y., Lee, L. W., & Ko, J. L. (2006). Ets2 binding site single nucleotide polymorphism at the hTERT gene promoter–effect on telomerase expression and telomere length maintenance in non-small cell lung cancer. European Journal of Cancer, 42(10), 1466-1474.
  • Huang, F. W., Hodis, E., Xu, M. J., Kryukov, G. V., Chin, L., & Garraway, L. A. (2013). Highly recurrent TERT promoter mutations in human melanoma. Science, 339(6122), 957-959.
  • Inada, E., Saitoh, I., Kubota, N., Iwase, Y., Kiyokawa, Y., Shibasaki, S., ... & Sato, M. (2019). piggy Bac transposon-based immortalization of human deciduous tooth dental pulp cells with multipotency and non-tumorigenic potential. International Journal of Molecular Sciences, 20(19), 4904.
  • Jafri, M. A., Ansari, S. A., Alqahtani, M. H., & Shay, J. W. (2016). Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine, 8(1), 69. https://doi.org/10.1186/s13073-016-0324-x
  • Johnson, B. E. (1995). Biologic and molecular prognostic factors—impact on treatment of patients with non-small cell lung cancer. Chest, 107(6), 287S-290S.
  • Jung, S. J., Kim, D. S., Park, W. J., Lee, H., Choi, I. J., Park, J. Y., & Lee, J. H. (2017). Mutation of the TERT promoter leads to poor prognosis of patients with non small cell lung cancer. Oncology Letters, 14(2), 1609-1614.
  • Kageler, L., & Aquilanti, E. (2024). Discovery of telomerase inhibitors: existing strategies and emerging innovations. Biochemical Society Transactions, 52(4), 1957-1968.
  • Kim, N. W., Piatyszek, M. A., Prowse, K. R., Harley, C. B., West, M. D., Ho, P. L., ... & Shay, J. W. (1994). Specific association of human telomerase activity with immortal cells and cancer. Science, 266(5193), 2011-2015.
  • Lewis, K. A., & Tollefsbol, T. O. (2016). Regulation of the telomerase reverse transcriptase subunit through epigenetic mechanisms. Frontiers in Genetics, 7, 83.
  • Liang, P., Xu, Y., Zhang, X., Ding, C., Huang, R., Zhang, Z., ... & Huang, J. (2015). CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein & Cell, 6(5), 363-372.
  • Lin, H. Y., & Park, J. Y. (2024). Epidemiology of cancer. In Anesthesia for oncological surgery (pp. 11-16). Cham: Springer International Publishing.
  • Liu, X., Bishop, J., Shan, Y., Pai, S., Liu, D., Murugan, A. K., ... & Xing, M. (2013). Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocrine-Related Cancer, 20(4), 603-610.
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Details

Primary Language English
Subjects Genetics (Other)
Journal Section Review
Authors

Onur Dülger 0000-0002-1155-7790

Publication Date April 30, 2025
Submission Date October 30, 2024
Acceptance Date January 29, 2025
Published in Issue Year 2025 Volume: 6 Issue: 1

Cite

APA Dülger, O. (2025). Telomerase reverse transcriptase promoter mutations in non-small cell lung cancer: Biology and clinical significance. Frontiers in Life Sciences and Related Technologies, 6(1), 60-64. https://doi.org/10.51753/flsrt.1576211
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