AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO025140085
Submit to EJMO
Cite this article
9
Download
151
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Exploring genetic and epigenetic alterations in hTERT gene in colorectal cancer

Meryem Jafari1,2,3 ,  Boutaina Addoum2* ,  Abdelilah Laraqui3 ,  Mohammed Oukabli4 ,  Ahmed Bounaim5 ,  Abdelmounim Ait Ali5 ,  Sidi Mohammed Bouchantouf5 ,  Noureddine Njoumi5 ,  Belkouchi Abdelkader6 ,  Fatima Zohra BenMoula6 ,  Hicham El Annaz3 ,  Khalid Ennibi3 ,  Imane Chaoui2 ,  Youssef Bakri1 ,  Mohammed Attaleb2
Show Less
1 Laboratory of Biology and Human Pathologies, Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University in Rabat, Rabat, Morocco
2 Biology and Medical Research Unit, National Center for Nuclear Energy, Sciences and Techniques, Rabat, Morocco
3 Clinical and Epidemiological Research Unit, Center of Virology, Infectious and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
4 Department of Pathology, Mohammed V Military Teaching Hospital of Rabat, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
5 Department of Digestive Surgery, Faculty of Medicine and Pharmacy, Mohammed V Military Hospital, Mohammed V University of Rabat, Rabat, Morocco
6 Department of Surgery, Ibn Sina Hospital, Rabat, Morocco
EJMO, 025140085 https://doi.org/10.36922/EJMO025140085
Received: 2 April 2025 | Revised: 22 April 2025 | Accepted: 13 May 2025 | Published online: 3 June 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Download PDF
Cite
XML
Abstract

Introduction: Colorectal cancer (CRC) is a heterogeneous and multifactorial malignancy driven by a series of genetic and epigenetic alterations. In this field, telomere/telomerase dysfunction contributes to CRC carcinogenesis by impairing genomic stability and cellular replication. Objective: This study aimed to evaluate genetic and epigenetic alterations in CRC by examining mutation rates in the human telomerase reverse transcriptase (hTERT) promoter region, relative telomere length (RTL), hTERT gene expression, and DNA methylation in the TERT hypermethylated oncological region (THOR). Methods: A total of 45 CRC and 34 adjacent normal tissue samples from Moroccan patients were analyzed using molecular approaches, such as Sanger sequencing, quantitative PCR (qPCR), reverse transcription qPCR (RT-qPCR), and methylation-specific PCR (MSP). Results: No mutations in the hTERT promoter region were identified. However, hypermethylation in the THOR region was reported in 82.2% of CRC samples and 79.4% of adjacent normal tissues. High hTERT expression was detected in 50% of CRC patients. In addition, telomere length was significantly shorter (p=0.002) in cancerous tissues (1.41 [1.36 – 1.43]) compared to normal mucosa (1.559 [1.46 – 1.63]), with an RTL ratio less than 1 (0.90 [0.86 – 0.95]). No significant differences were found between clinicopathological features and hTERT expression, THOR methylation, or RTL, except for a significant correlation between THOR hypermethylation and smaller tumor size (p=0.017) and between THOR methylation and RTL in CRC tissues (p=0.034). Conclusion: These results suggest that telomere lengthening is crucial for CRC initiation and progression, and cancer cells tend to shorten telomeres to maintain the chromosomal instability (CIN) required for tumor progression. Further research is needed to elucidate the mechanisms underlying telomere shortening in CRC and understand the role of telomerase/telomere complex in CRC initiation and progression, which could provide new diagnostic, prognostic, and therapeutic targets.

Keywords
Colorectal cancer
THOR methylation
hTERT promoter mutation
Gene expression
Telomere length
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer; 2024. Available from: https://gco.iarc. who.int/today [Last accessed on 2025 Mar 10].

 

  1. El Alami Y, Essangri H, Majbar MA, et al. Psychometric validation of the Moroccan version of the EORTC QLQ-C30 in colorectal cancer patients: Cross-sectional study and systematic literature review. BMC Cancer. 2021;21(1):99. doi: 10.1186/s12885-021-07793-w

 

  1. Fidler MM, Bray F, Vaccarella S, Soerjomataram I. Assessing global transitions in human development and colorectal cancer incidence. Int J Cancer. 2017;140(12):2709-2715. doi: 10.1002/ijc.30686

 

  1. Ministère de la Santé. Registre-des-Cancers-de-la-Region-du- Grand-Casablanca-2018-2021. Available from: https://www. contrelecancer.ma/site-media/uploaded-files/registre-des-cancers-de-la-region-du-grand-casablanca-2018-2021-1- nj8oed2.pdf [Last accessed on 2025 Feb 6].

 

  1. Currais P, Rosa I, Claro I. Colorectal cancer carcinogenesis: From bench to bedside. World J Gastrointest Oncol. 2022;14(3):654-663. doi: 10.4251/wjgo.v14.i3.654

 

  1. Tariq K, Ghias K. Colorectal cancer carcinogenesis: A review of mechanisms. Cancer Biol Med. 2016;13(1):120-135. doi: 10.28092/j.issn.2095-3941.2015.0103

 

  1. Nguyen LH, Goel A, Chung DC. Pathways of colorectal carcinogenesis. Gastroenterology. 2020;158(2):291-302. doi: 10.1053/j.gastro.2019.08.059

 

  1. Bertorelle R, Rampazzo E, Pucciarelli S, Nitti D, Rossi AD. Telomeres, telomerase and colorectal cancer. World J Gastroenterol. 2014;20(8):1940-1950. doi: 10.3748/wjg.v20.i8.1940

 

  1. Gertler R, Rosenberg R, Stricker D, et al. Telomere length and human telomerase reverse transcriptase expression as markers for progression and prognosis of colorectal carcinoma. J Clin Oncol. 2004;22(10):1807-1814. doi: 10.1200/JCO.2004.09.160

 

  1. Pellatt AJ, Wolff RK, Herrick J, Lundgreen A, Slattery ML. TERT’s role in colorectal carcinogenesis. Mol Carcinog. 2013;52(7):507-513. doi: 10.1002/mc.21885

 

  1. Zinn RL, Pruitt K, Eguchi S, Baylin SB, Herman JG. HTERT is expressed in cancer Cell lines despite promoter DNA methylation by preservation of unmethylated DNA and active chromatin around the transcription start site. Cancer Res. 2007;67(1):194-201. doi: 10.1158/0008-5472.CAN-06-3396

 

  1. Gong C, Yang H, Wang S, et al. HTERT promotes CRC proliferation and migration by recruiting YBX1 to increase NRF2 expression. Front Cell Dev Biol. 2021;9:658101. doi: 10.3389/fcell.2021.658101

 

  1. El Azzouzi M, El Ahanidi H, Hassan I, et al. Comprehensive behavioural assessment of TERT in bladder cancer. Urol Oncol Semin Orig Investing. 2024;42(12):451.e19-451.e29. doi: 10.1016/j.urolonc.2024.06.024

 

  1. El Ahanidi H, El Azzouzi M, Hafidi Alaoui C, et al. Immune checkpoint and telomerase crosstalk is mediated by miRNA-138 in bladder cancer. Front Oncol. 2021;11:795242. doi: 10.3389/fonc.2021.795242

 

  1. Nault JC, Mallet M, Pilati C, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013;4:2218.doi: 10.1038/ncomms3218

 

  1. Brás JP, Jesus TT, Prazeres H, Lima J, Soares P, Vinagre J. TERTmonitor-qPCR detection of TERTp mutations in glioma. Genes (Basel). 2023;14(9):1693. doi: 10.3390/genes14091693

 

  1. Cruvinel-Carloni A, Yamane L, Scapulatempo-Neto C, Guimarães D, Reis RM. Absence of TERT promoter mutations in colorectal precursor lesions and cancer. Genet Mol Biol. 2018;41(1):82-84. doi: 10.1590/1678-4685-GMB-2017-0133

 

  1. Akıncılar SC, Chua JYH, Ng QF, et al. Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer. Nucleic Acids Res. 2023;51(1):1-16. doi: 10.1093/nar/gkac479

 

  1. El Zarif T, Machaalani M, Nawfal R, et al. TERT promoter mutations frequency across race, sex, and cancer type. Oncologist. 2023;29(1):8-14. doi: 10.1093/oncolo/oyad208

 

  1. Ayiomamitis GD, Notas G, Zaravinos A, et al. Differences in telomerase activity between colon and rectal cancer. Can J Surg. 2014;57(3):199-208. doi: 10.1503/cjs.031312

 

  1. Rampazzo E, Bertorelle R, Serra L, et al. Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers. Br J Cancer. 2010;102(8):1300-1305. doi: 10.1038/sj.bjc.6605644

 

  1. Valls-Bautista C, Bougel S, Piñol-Felis C, Viñas-Salas J, Benhattar J. HTERT methylation is necessary but not sufficient for telomerase activity in colorectal cells. Oncol Lett. 2011;2(6):1257-1260. doi: 10.3892/ol.2011.386

 

  1. Roger L, Jones RE, Heppel NH, Williams GT, Sampson JR, Baird DM. Extensive telomere erosion in the initiation of colorectal adenomas and its association with chromosomal instability. J Natl Cancer Inst. 2013;105(16):1202-1211. doi: 10.1093/jnci/djt191

 

  1. Balc’h EL, Grandin N, Demattei MV, et al. Measurement of telomere length in colorectal cancers for improved molecular diagnosis. Int J Mol Sci. 2017;18(9):1871. doi: 10.3390/ijms18091871

 

  1. Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual. New York: Cold Spring Harbor Laboratory; 1989.

 

  1. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002;30(10):e47. doi: 10.1093/nar/30.10.e47

 

  1. Jamovi Open Statistical Software for the Desktop and Cloud. Available from: https://www.jamovi.org [Last accessed on 2024 Dec 15].

 

  1. Shay JW, Wright WE. Role of telomeres and telomerase in cancer. Semin Cancer Biol. 2011;21(6):349-353. doi: 10.1016/j.semcancer.2011.10.001

 

  1. Bertorelle R, De Rossi A. Telomerase as biomarker in colorectal cancer. In: Preedy VR, Patel VB, editors. Biomarkers in Cancer. Biomarkers in Disease: Methods, Discoveries and Applications. Netherlands: Springer; 2015. p. 659-683. doi: 10.1007/978-94-007-7681-4-2

 

  1. Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A. 2013;110(15):6021-6026. doi: 10.1073/pnas.1303607110

 

  1. Lee DD, Komosa M, Sudhaman S, et al. Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer. J Clin Invest. 2021;131(21):e146915. doi: 10.1172/JCI146915

 

  1. Siraj AK, Bu R, Iqbal K, et al. Telomerase reverse transcriptase promoter mutations in cancers derived from multiple organ sites among middle eastern population. Genomics. 2020;112(2):1746-1753. doi: 10.1016/j.ygeno.2019.09.017

 

  1. Faleiro I, Apolónio JD, Price AJ, et al. The TERT hypermethylated oncologic region predicts recurrence and survival in pancreatic cancer. Future Oncol Lond Engl. 2017;13(23):2045-2051. doi: 10.2217/fon-2017-0167

 

  1. Leão R, Lee D, Figueiredo A, et al. Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer. Int J Cancer. 2019;144(7):1676-1684. doi: 10.1002/ijc.31935

 

  1. Liu L, Liu C, Fotouhi O, et al. TERT promoter hypermethylation in gastrointestinal cancer: A potential stool biomarker. Oncologist. 2017;22(10):1178-1188. doi: 10.1634/theoncologist.2017-0064

 

  1. Lee DD, Leão R, Komosa M, et al. DNA hypermethylation within TERT promoter upregulates TERT expression in cancer. J Clin Invest. 2019;129(1):223-229. doi: 10.1172/JCI121303

 

  1. Niknam M, Naghibalhossaini F, Zamani M, Hosseini SV, Mokarram P. The effects of thymidylate synthase 3’UTR genotype on methylation of tumor-specific genes promoter in 22 colorectal cancer patients from southern Iran. Mol Biol Res Commun. 2024;13(2):89-102. doi: 10.22099/mbrc.2023.48009.1850

 

  1. Saleh S, King-Yin Lam A, Ho YH. Real-time PCR quantification of human telomerase reverse transcriptase (hTERT) in colorectal cancer. Pathology (Phila). 2008;40(1):25-30. doi: 10.1080/00313020701716425

 

  1. Gertler R, Rosenberg R, Stricker D, et al. Prognostic potential of the telomerase subunit human telomerase reverse transcriptase in tumor tissue and nontumorous mucosa from patients with colorectal carcinoma. Cancer. 2002;95(10):2103-2111. doi: 10.1002/cncr.10939

 

  1. Aljarbou F, Almousa N, Bazzi M, et al. The expression of telomere-related proteins and DNA damage response and their association with telomere length in colorectal cancer in Saudi patients. PLoS One. 2018;13(6):e0197154. doi: 10.1371/journal.pone.0197154

 

  1. Valls C, Piñol C, Reñé JM, Buenestado J, Viñas J. Telomere length is a prognostic factor for overall survival in colorectal cancer. Colorectal Dis. 2011;13(11):1265-1272. doi: 10.1111/j.1463-1318.2010.02433.x

 

  1. Suraweera N, Mouradov D, Li S, et al. Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer. Oncotarget. 2016;7(24):36474-36488. doi: 10.18632/oncotarget.9015

 

  1. Fernández-Marcelo T, Sánchez-Pernaute A, Pascua I, et al. Clinical relevance of telomere status and telomerase activity in colorectal cancer. PLoS One. 2016;11(2):e0149626. doi: 10.1371/journal.pone.0149626

 

  1. Kroupa M, Rachakonda SK, Liska V, et al. Relationship of telomere length in colorectal cancer patients with cancer phenotype and patient prognosis. Br J Cancer. 2019;121(4):344-350. doi: 10.1038/s41416-019-0525-3

 

  1. Kroupa M, Kubecek O, Tomasova K, et al. The dynamics of telomere length in primary and metastatic colorectal cancer lesions. Sci Rep. 2023;13(1):9097. doi: 10.1038/s41598-023-35835-9

 

  1. Loukopoulou C, Nikolouzakis T, Koliarakis I, Vakonaki E, Tsiaoussis J. Telomere length and telomerase activity as potential biomarkers for gastrointestinal cancer. Cancers (Basel). 2024;16(19):3370. doi: 10.3390/cancers16193370

 

  1. Augustine TA, Baig M, Sood A, et al. Telomere length is a novel predictive biomarker of sensitivity to anti-EGFR therapy in metastatic colorectal cancer. Br J Cancer. 2015;112(2):313-318. doi: 10.1038/bjc.2014.561

 

  1. Niiyama H, Mizumoto K, Sato N, et al. Quantitative analysis of hTERT mRNA expression in colorectal cancer. Am J Gastroenterol. 2001;96(6):1895-1900. doi: 10.1111/j.1572-0241.2001.03890.x
Share
Back to top
Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept