Common telomerase reverse transcriptase promoter mutations in hepatocellular carcinomas from different geographical locations

World J Gastroenterol. 2015 Jan 7;21(1):311-7. doi: 10.3748/wjg.v21.i1.311.


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

Publication types

  • Comparative Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Africa / epidemiology
  • Asia / epidemiology
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / epidemiology
  • Carcinoma, Hepatocellular / genetics*
  • DNA Mutational Analysis
  • Europe / epidemiology
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Hep G2 Cells
  • Heterozygote
  • Humans
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / epidemiology
  • Liver Neoplasms / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic*
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Telomerase / genetics*


  • Biomarkers, Tumor
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • TERT protein, human
  • Telomerase