title: The TERT promoter SNP rs2853669 decreases E2F1 transcription factor binding and increases mortality and recurrence risks in liver cancer.
abstract: A common single-nucleotide polymorphism in the telomerase reverse transcriptase (TERT) promoter, rs2853669 influences patient survival rates and the risk of developing cancer. Recently, several lines of evidence suggest that the rs2853669 suppresses TERT promoter mutation-mediated TERT expression levels and cancer mortality as well as recurrence rates. However, no reports are available on the impact of rs2853669 on TERT expression in hepatocellular carcinoma (HCC) and its association with patient survival. Here, we found that HCC-related overall and recurrence-free survival rates were not associated with TERT promoter mutation individually, but rs2853669 and the TERT promoter mutation in combination were associated with poor survival rates. TERT mRNA expression and telomere fluorescence levels were greater in patients with HCC who had both the combination. The combination caused TERT promoter methylation through regulating the binding of DNA methyltransferase 1 and histone deacetylase 1 to the TERT promoter in HCC cell lines. The TERT expression level was significantly higher in HCC tumor with a methylated promoter than in that with an unmethylated promoter. In conclusion, we demonstrate a substantial role for the rs2853669 in HCC with TERT promoter mutation, which suggests that the combination of the rs2853669 and the mutation indicate poor prognoses in liver cancer.
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanak-gu, Seoul, 151-747, South Korea.
authors.forename: Eunkyong
authors.initials: E
authors.lastname: Ko
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanak-gu, Seoul, 151-747, South Korea.
authors.forename: Hyun-Wook
authors.initials: HW
authors.lastname: Seo
authors.affiliation: Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seocho-Gu, Seoul, 133-782, South Korea.
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Jung
authors.affiliation: Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, 152-703, South Korea.
authors.forename: Baek-hui
authors.initials: BH
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanak-gu, Seoul, 151-747, South Korea.
authors.forename: Guhung
authors.initials: G
authors.lastname: Jung
mesh_terms: D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D008969:Molecular Sequence Data; D009364:Neoplasm Recurrence, Local; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D019098:Telomerase / Q000235:genetics*
chemical_list: D050687:E2F1 Transcription Factor; C509186:TERT protein, human; D019098:Telomerase
keywords: A TERT transcription repressor; TERT promoter mutation; mechanism for regulation of SNP-dependent TERT promoter activity; risk of hepatocellular carcinoma (HCC)-related mortality and recurrence; single-nucleotide polymorphism at telomerase reverse transcriptase (TERT) promoter