Observational Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 7, 2015; 21(1): 311-317
Published online Jan 7, 2015. doi: 10.3748/wjg.v21.i1.311
Common telomerase reverse transcriptase promoter mutations in hepatocellular carcinomas from different geographical locations
Dilek Cevik, Gokhan Yildiz, Mehmet Ozturk
Dilek Cevik, Gokhan Yildiz, Mehmet Ozturk, BilGen Genetics and Biotechnology Center, Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey
Dilek Cevik, Gokhan Yildiz, Mehmet Ozturk, Centre de Recherche Inserm-Université Joseph Fourrier U823, La Tronche 38706, France
Mehmet Ozturk, Advanced Biomedical Research Center, Dokuz Eylul University, Izmir 35340, Turkey
Author contributions: Cevik D and Yildiz G performed the experiments; Ozturk M designed and coordinated the study; Cevik D and Ozturk M wrote the manuscript.
Supported by TUBITAK, the Scientific and Technological Research Council of Turkey, No. 113S389, TUBITAK (BIDEB-2211), TUBITAK (BIDEB-2211 and BIDEB-2214) and EMBO short term fellowships
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Mehmet Ozturk, PhD, Professor of Medical Biology, Advanced Biomedical Research Center, Dokuz Eylul University, Balcova, Izmir 35340, Turkey. mehmet.ozturk@deu.edu.tr
Telephone: +90-232-4126501 Fax: +90-232-4648135
Received: April 12, 2014
Peer-review started: April 12, 2014
First decision: May 13, 2014
Revised: June 3, 2014
Accepted: July 11, 2014
Article in press: July 11, 2014
Published online: January 7, 2015
Processing time: 269 Days and 17.6 Hours
Abstract

AIM: To determine the mutation status of human telomerase reverse transcriptase gene (TERT) promoter region in hepatocellular carcinoma (HCC) from different geographical regions.

METHODS: We analyzed the genomic DNA sequences of 59 HCC samples comprising 15 cell lines and 44 primary tumors, collected from patients living in Asia, Europe and Africa. We amplified a 474 bp DNA fragment of the promoter region of TERT gene including the 1295228 and 1295250 sequence of chromosome 5 by using PCR. Amplicons were then sequenced by Sanger technique and the sequence data were analyzed with by using DNADynamo software in comparison with wild type TERT gene sequence as a reference.

RESULTS: The TERT mutations were found highly frequent in HCC. Eight of the fifteen tested cell lines displayed C228T mutation, and one had C250T mutation with a mutation frequency up to 60%. All of the mutations were heterozygous and mutually exclusive. Ten out of forty-four tumors displayed C228T mutation, and additional five tumors had C250T mutation providing evidence for mutation frequency of 34% in primary tumors. Considering the geographic origins of HCC tumors tested, TERT promoter mutation frequencies were higher in African (53%), when compared to non-African (24%) tumors (P = 0.056). There was also a weak inverse correlation between TERT promoter mutations and murine double minute 2 single nucleotide polymorphism 309 TG polymorphism (P = 0.058). Mutation frequency was nearly two times higher in established HCC cell lines (60%) compared to the primary tumors (34%).

CONCLUSION: TERT promoter is one of most frequent mutational targets in liver cancer, and hepatocellular carcinogenesis is highly associated with the loss of telomere-dependent cellular senescence control.

Keywords: Hepatocellular carcinoma; Liver cancer; Telomerase reverse transcriptase; Promoter mutation; Cellular immortality; Telomerase reverse transcriptase gene

Core tip: Our study demonstrated that telomerase reverse transcriptase (TERT) promoter mutations are present in hepatocellular carcinomas (HCCs) from different geographical regions, and the highest frequency was observed in tumors from Africa. These mutations occur both primarily as C228T mutation and as C250T mutation. These results also provide evidence for TERT mutations as a common trait of HCC regardless of their geographical location.