The TERT promoter mutation incidence is modified by germline TERT rs2736098 and rs2736100 polymorphisms in hepatocellular carcinoma

Abstract

Telomerase activation via induction of the catalytic component telomerase reverse transcriptase (TERT) plays essential roles in malignant transformation. TERT promoter-activating mutations were recently identified as a novel mechanism to activate telomerase in hepatocellular carcinoma (HCC) and many other malignancies. In addition, single nucleotide polymorphisms (SNPs) in the TERT rs2736098 and rs2736100 are significantly associated with cancer susceptibility. It is currently unclear whether different germline TERT variants modify TERT promoter mutations. Here we analyzed the TERT promoter status and genotyped the TERT SNPs at rs2736098 and rs2736100 in patients with HCC. Thirty percent of HCCs harbored TERT promoter mutations and there was a significant difference in rs2736098 and rs2736100 genotypes between wt and mutant TERT promoter-bearing HCC tumors (P = 0.007 and 0.018, respectively). For rs2736100, the cancer risk genotype CC was significantly associated with a reduced incidence of TERT promoter mutations compared to AA + AC variants [Odds ratio (OR): 0.181, 95% Confidence interval (CI): 0.0543–0.601, P = 0.004]. The rs2736098_CT genotype was significantly associated with the TERT promoter mutation-positive tumors compared to the TT genotype (OR: 5.391, 95% CI: 1.234–23.553, P = 0.025). These differences in genotype distribution did not differ between patients with a wt TERT promoter and controls. The presence of TERT promoter mutations was not associated with clinico-pathological variables. Taken together, the germline TERT genetic background may significantly affect the onset of TERT promoter mutations in HCCs, which provides a better understanding of HCC-related TERT promoter mutations and telomerase regulation in cancer.

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

“…They observed that the spontaneous acquisition of TERT promoter mutations was selected for in blood cells from non-tumor individuals with very short telomere due to germline defects in the TERT protein or other telomerase components [64]. We found that the germline variants at the TERT locus significantly affected the TERT promoter mutation rate in HCC patients, and the TERT rs2736100-CC cancer risk genotype was more frequently seen in patients with a wt TERT promoter [65]. This variant is known to upregulate TERT expression, thereby counteracting telomere shortening [66].…”

Association Between TERT rs2736098 Polymorphisms and Cancer Risk-A Meta-Analysis

“…Among the remaining 51 articles, 13 were 13 were meta-analyses, four were conferences, three reported incomplete data, two had no controls, and one had duplicated data. Finally, 15,837 cases and 19,263 controls of 31 studies in 28 articles were included in this meta-analysis (Savage et al, 2007 ; Choi et al, 2009 ; Liu et al, 2010 ; Chen et al, 2011 ; Ding et al, 2011 ; Gago-Dominguez et al, 2011 ; Jaworowska et al, 2011 ; Hofer et al, 2012 ; Wang et al, 2012 , 2016 ; Li et al, 2013 ; Ma et al, 2013 ; Wu et al, 2013 ; Zhang et al, 2013 , 2014 ; Gao et al, 2014 ; Hashemi et al, 2014 ; Singh et al, 2014 ; Su et al, 2014 ; Yin et al, 2014 ; Zhao et al, 2014 ; Jannuzzi et al, 2015 ; Carkic et al, 2016 ; de Martino et al, 2016 ; Oztas et al, 2016 ; Xing et al, 2016 ; Xiao and He, 2017 ; Yuan et al, 2017 ). The genotyping methods included TaqMan PCR, PCR-RFLP, Sequenom, and LDR.…”

“…With regard to hepatocellular carcinoma, the rs2736098 AA genotype was identified as an independent hereditary factor associated with carcinoma susceptibility in the Chinese population by Zhang et al ( 2013 ) and Su et al ( 2014 ). However, another study failed to demonstrate such genetic susceptibility, reporting only a significant association between the rs2736098 GA genotype and TERT promoter mutation-positive tumors compared with the AA genotype (Yuan et al, 2017 ). The current meta-analysis revealed that the TERT rs2736098 AA genotype was significantly associated with an increased risk of hepatocellular carcinoma in the heterozygous and dominant models.…”

TERT rs2736098 (Ex2-659G>A) polymorphism and cancer susceptibility: evidence from a comprehensive meta-analysis

“…2 additional publications were further extracted by manually screening the references of the retrieval articles [ 21 , 22 ]. As a result, 33 studies including 32 publications were used for investigation [ 13 , 16 , 21 – 50 ]. The general workflow of selecting the eligible studies was graphically shown in Figure 1 .…”