The investigation of new mutations in telomerase reverse transcriptase promoter region in association with bladder cancer

Hanan Ramadhan; Safaa Abdulabass Alhamedi; Ammar Ihsan Awadh; Omar Farooq Abdul-Rasheed; Safaa Mezban

doi:10.12991/jrespharm.1796220

The investigation of new mutations in telomerase reverse transcriptase promoter region in association with bladder cancer

Abstract

Telomerase reverse transcriptase (TERT) is frequently reactivated in Urothelial Bladder Cancer (UBC) due to changes in its promoter region, rendering it a vital target for cancer-specific genetic modifications. The present work was aimed to investigate the TERT promoter region to explore the mutations that may affect the incidence and the pathogenesis of Urothelial Bladder Cancer in a study included 59 patients subjected to either transurethral bladder resection or radical cystectomy from which serum and tissue samples were obtained and the DNA extraction was performed with the use of purification Promega kit and the amplified DNA samples were sequenced by Sanger sequencing using an automated DNA sequencer to determine TERT gene promoter mutations. The results of the study showed that 47 patients out of 59 showed a mutation at the position -129 (1295233), 44 of them with c.232_233insA and 3 patients with a C233A mutation. Sixteen patients of the 59 patients subjected to the genetic analysis showed a mutation at the position -109 (1295213) in the TERT promoter region, the later mutation showed to be associated significantly with the grade of the reaction wheras the former mutation didn’t show that. On the other hand the two novel mutation showed a non-significant association with the levels of hTERT, age, gender, muscle invasiveness, recurrence and smoking and it was concluded from that the mutation in the TERT promoter region my have an effect on the TERT expression that participate in the bladder cancer pathogenisis which need further studies.

Keywords

References

[1] Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, Znaor A, Bray F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941-1953. https://doi.org/10.1002/ijc.31937
[2] Alrubaye YSJ, Mohammed MB, Abdulamir HA. Exosome and breast cancer. Res J Pharm Technol. 2022;15(3):1393-1397. https://www.doi.org/10.52711/0974-360X.2022.00232
[3] van Rhijn BW, Burger M, Lotan Y, Solsona E, Stief CG, Sylvester RJ, Witjes JA, Zlotta AR. Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol. 2009;56(3):430-442. https://doi.org/10.1016/j.eururo.2009.06.028
[4] Netto GJ. Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet? Nat Rev Urol. 2011;9(1):41-51. https://doi.org/10.1038/nrurol.2011.193
[5] Günes C, Rudolph KL. The role of telomeres in stem cells and cancer. Cell. 2013;152(3):390-393. https://doi.org/10.1016/j.cell.2013.01.010
[6] Kyo S, Takakura M, Fujiwara T, Inoue M. Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. Cancer Sci. 2008;99(8):1528-1538. https://doi.org/10.1111/j.1349-7006.2008.00878.x
[7] Wan S, Liu X, Hua W, Xi M, Zhou Y, Wan Y. The role of telomerase reverse transcriptase (TERT) promoter mutations in prognosis in bladder cancer. Bioengineered. 2021;12(1):1495-1504. https://doi.org/10.1080/21655979.2021.1915725
[8] Vinagre J, Almeida A, Pópulo H, Batista R, Lyra J, Pinto V, Coelho R, Celestino R, Prazeres H, Lima L, Melo M, da Rocha AG, Preto A, Castro P, Castro L, Pardal F, Lopes JM, Santos LL, Reis RM, Cameselle-Teijeiro J, Sobrinho-Simões M, Lima J, Máximo V, Soares P. Frequency of TERT promoter mutations in human cancers. Nat Commun. 2013;4:2185. https://doi.org/10.1038/ncomms3185

[9] Roggisch J, Ecke T, Koch S. Molecular identification of telomerase reverse transcriptase (TERT) promotor mutations in primary and recurrent tumors of invasive and noninvasive urothelial bladder cancer. Urol Oncol. 2020;38(3):77.e17-77.e25. https://doi.org/10.1016/j.urolonc.2019.08.007
[10] Pérez González S, Heredia-Soto V, Girón de Francisco M, Pérez-Fernández E, Casans-Francés R, Mendiola Sabio M, González-Peramato P. Telomerase reverse transcriptase-promoter mutation in young patients with bladder tumors. Curr Issues Mol Biol. 2024;46(4):2845-2855. https://doi.org/10.3390/cimb46040178
[11] Boscolo-Rizzo P, Giunco S, Rampazzo E, Brutti M, Spinato G, Menegaldo A, Stellin M, Mantovani M, Bandolin L, Rossi M, Del Mistro A, Tirelli G, Dei Tos AP, Guerriero A, Niero M, Da Mosto MC, Polesel J, De Rossi A. TERT promoter hotspot mutations and their relationship with TERT levels and telomere erosion in patients with head and neck squamous cell carcinoma. J Cancer Res Clin Oncol. 2020;146(2):381-389. https://doi.org/10.1007/s00432-020-03130-z
[12] Rachakonda PS, Hosen I, de Verdier PJ, Fallah M, Heidenreich B, Ryk C, Wiklund NP, Steineck G, Schadendorf D, Hemminki K, Kumar R. TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism. Proc Natl Acad Sci U S A. 2013;110(43):17426-17431. https://doi.org/10.1073/pnas.1310522110
[13] Jahnson S, Söderkvist P, Aljabery F, Olsson HJBi. Telomerase reverse transcriptase mutation and the p53 pathway in T1 urinary bladder cancer. BJU Int. 2022;129(5):601-619. https://doi.org/10.1111/bju.15490
[14] Siraj AK, Bu R, Iqbal K, Parvathareddy SK, Siraj N, Siraj S, Diaz MRF, Rala DR, Benito AD, Sabido MA, Al-Rasheed M, Al-Obaisi KAS, Al-Haqawi W, Victoria IG, Al Balawy W, Abedalthagafi M, Wakil SM, Ajarim D, Mohammed S, Alhussain T, Tulbah A, Al-Badawi IA, Al-Dayel F, Al-Kuraya KS. Telomerase reverse transcriptase promoter mutations in cancers derived from multiple organ sites among middle eastern population. Genomics. 2020;112(2):1746-1753. https://doi.org/10.1016/j.ygeno.2019.09.017
[15] Wu S, Huang P, Li C, Huang Y, Li X, Wang Y, Chen C, Lv Z, Tang A, Sun X, Lu J, Li W, Zhou J, Gui Y, Zhou F, Wang D, Cai Z. Telomerase reverse transcriptase gene promoter mutations help discern the origin of urogenital tumors: a genomic and molecular study. Eur Urol. 2014;65(2):274-277. https://doi.org/10.1016/j.eururo.2013.10.038
[16] Giedl J, Rogler A, Wild A, Riener MO, Filbeck T, Burger M, Rümmele P, Hurst C, Knowles M, Hartmann A, Zinnall U, Stoehr R. TERT Core Promotor Mutations in Early-Onset Bladder Cancer. J Cancer. 2016;7(8):915-920. https://doi.org/10.7150/jca.15006
[17] Oversoe SK, Clement MS, Pedersen MH, Weber B, Aagaard NK, Villadsen GE, Grønbæk H, Hamilton-Dutoit SJ, Sorensen BS, Kelsen J. TERT promoter mutated circulating tumor DNA as a biomarker for prognosis in hepatocellular carcinoma. Scand J Gastroenterol. 2020;55(12):1433-1440. https://doi.org/10.1080/00365521.2020.1837928
[18] Blateau P, Coyaud E, Laurent E, Béganton B, Ducros V, Chauchard G, Vendrell JA, Solassol J. TERT promoter mutation as an ındependent prognostic marker for poor prognosis MAPK ınhibitors-treated melanoma. Cancers (Basel). 2020;12(8):2224. https://doi.org/10.3390/cancers12082224
[19] Batista R, Lima L, Vinagre J, Pinto V, Lyra J, Máximo V, Santos L, Soares P. TERT promoter mutation as a potential predictive biomarker in BCG-treated bladder cancer patients. Int J Mol Sci. 2020;21(3):947. https://doi.org/10.3390/ijms21030947
[20] Allory Y, Beukers W, Sagrera A, Flández M, Marqués M, Márquez M, van der Keur KA, Dyrskjot L, Lurkin I, Vermeij M, Carrato A, Lloreta J, Lorente JA, Carrillo-de Santa Pau E, Masius RG, Kogevinas M, Steyerberg EW, van Tilborg AAG, Abas C, Orntoft TF, Zuiverloon TCM, Malats N, Zwarthoff EC, Real FX. Telomerase Reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome. Eur Urol. 2014;65(2):360-366. https://doi.org/10.1016/j.eururo.2013.08.052
[21] Bournaud C, Descotes F, Decaussin-Petrucci M, Berthiller J, de la Fouchardière C, Giraudet AL, Bertholon-Gregoire M, Robinson P, Lifante JC, Lopez J, Borson-Chazot F. TERT promoter mutations identify a high-risk group in metastasis-free advanced thyroid carcinoma. Eur J Cancer. 2019;108:41-49. https://doi.org/10.1016/j.ejca.2018.12.003
[22] Griewank KG, Murali R, Puig-Butille JA, Schilling B, Livingstone E, Potrony M, Carrera C, Schimming T, Möller I, Schwamborn M, Sucker A, Hillen U, Badenas C, Malvehy J, Zimmer L, Scherag A, Puig S, Schadendorf D. TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma. J Natl Cancer Inst. 2014;106(9):dju246. https://doi.org/10.1093/jnci/dju246
[23] Porika M, Tippani R, Mohammad A, Bollam SR, Panuganti SD, Abbagani S. Evaluation of serum human telomerase reverse transcriptase as a novel marker for cervical cancer. Int J Biol Markers. 2011;26(1):22-26. https://doi.org/10.5301/jbm.2011.6352
[24] Porika M, Tippani R, Bollam SR, Panuganti SD, Thamidala C, Abbagani S. Serum human telomerase reverse transcriptase: a novel biomarker for breast cancer diagnosis. Int J Clin Oncol. 2011;16(6):617-622. https://doi.org/10.1007/s10147-011-0230-6
[25] Abdulhussein HA, Alwasiti EA, Khiro NK. The role of VEGF levels in the differentiation between malignant and benign breast tumor. J Res Pharm. 2024; 28(3): 603-611. http://dx.doi.org/10.29228/jrp.721
[26] Jabur MS, Manna MJ, Mohammed HR, Baqir LS, Abdulamir HA. Ocular hypotensive effect for the topical amlodipine 0.5% eye drop. Lat Am J Pharm. 2023;42:311-314.

Details

Primary Language

English

Subjects

Pharmacology and Pharmaceutical Sciences (Other)

Journal Section

Research Article

Authors

Hanan Ramadhan ^*
0000-0002-9945-2028
Iraq

Safaa Abdulabass Alhamedi This is me
0000-0001-6714-8446
Iraq

Ammar Ihsan Awadh This is me
0000-0002-2889-1656
Iraq

Omar Farooq Abdul-Rasheed This is me
0000-0003-3016-9176
Iraq

Safaa Mezban This is me
0000-0001-7565-6395
Iraq

Publication Date

November 2, 2025

Submission Date

December 25, 2024

Acceptance Date

March 7, 2025

Published in Issue

Year 2025 Volume: 29 Number: 6

DOI

https://doi.org/10.12991/jrespharm.1796220

IZ

https://izlik.org/JA22DU42YH

Cite

RIS / Bibtex

APA

Ramadhan, H., Alhamedi, S. A., Awadh, A. I., Abdul-Rasheed, O. F., & Mezban, S. (2025). The investigation of new mutations in telomerase reverse transcriptase promoter region in association with bladder cancer. Journal of Research in Pharmacy, 29(6), 2230-2238. https://doi.org/10.12991/jrespharm.1796220

AMA

1.Ramadhan H, Alhamedi SA, Awadh AI, Abdul-Rasheed OF, Mezban S. The investigation of new mutations in telomerase reverse transcriptase promoter region in association with bladder cancer. J. Res. Pharm. 2025;29(6):2230-2238. doi:10.12991/jrespharm.1796220

Chicago

Ramadhan, Hanan, Safaa Abdulabass Alhamedi, Ammar Ihsan Awadh, Omar Farooq Abdul-Rasheed, and Safaa Mezban. 2025. “The Investigation of New Mutations in Telomerase Reverse Transcriptase Promoter Region in Association With Bladder Cancer”. Journal of Research in Pharmacy 29 (6): 2230-38. https://doi.org/10.12991/jrespharm.1796220.

EndNote

Ramadhan H, Alhamedi SA, Awadh AI, Abdul-Rasheed OF, Mezban S (November 1, 2025) The investigation of new mutations in telomerase reverse transcriptase promoter region in association with bladder cancer. Journal of Research in Pharmacy 29 6 2230–2238.

IEEE

[1]H. Ramadhan, S. A. Alhamedi, A. I. Awadh, O. F. Abdul-Rasheed, and S. Mezban, “The investigation of new mutations in telomerase reverse transcriptase promoter region in association with bladder cancer”, J. Res. Pharm., vol. 29, no. 6, pp. 2230–2238, Nov. 2025, doi: 10.12991/jrespharm.1796220.

ISNAD

Ramadhan, Hanan - Alhamedi, Safaa Abdulabass - Awadh, Ammar Ihsan - Abdul-Rasheed, Omar Farooq - Mezban, Safaa. “The Investigation of New Mutations in Telomerase Reverse Transcriptase Promoter Region in Association With Bladder Cancer”. Journal of Research in Pharmacy 29/6 (November 1, 2025): 2230-2238. https://doi.org/10.12991/jrespharm.1796220.

JAMA

1.Ramadhan H, Alhamedi SA, Awadh AI, Abdul-Rasheed OF, Mezban S. The investigation of new mutations in telomerase reverse transcriptase promoter region in association with bladder cancer. J. Res. Pharm. 2025;29:2230–2238.

MLA

Ramadhan, Hanan, et al. “The Investigation of New Mutations in Telomerase Reverse Transcriptase Promoter Region in Association With Bladder Cancer”. Journal of Research in Pharmacy, vol. 29, no. 6, Nov. 2025, pp. 2230-8, doi:10.12991/jrespharm.1796220.

Vancouver

1.Hanan Ramadhan, Safaa Abdulabass Alhamedi, Ammar Ihsan Awadh, Omar Farooq Abdul-Rasheed, Safaa Mezban. The investigation of new mutations in telomerase reverse transcriptase promoter region in association with bladder cancer. J. Res. Pharm. 2025 Nov. 1;29(6):2230-8. doi:10.12991/jrespharm.1796220