TERT has been reported to be the most common mutated gene in HCC patients, with the frequency ranged from 51–60% [11–14]. In this study, the mutation frequency of TERT was 42.0%, which was lower than TP53 (56.8%). The difference between our study and previous studies may be attributed to the different hepatitis backgrounds. In previous studies, HCV infection was the most common in enrolled patients [11–14]. While in our study, all patients were HBsAg positive and without HCV infection. HBV could active the telomerase by inverting into the TERT, which provided an alternative mechanism of reactivating telomerase and might cause the reduced rate of TERT mutations [21, 22].
In our study, TERT mutations consisted of promoter mutation, substitution, amplification and rearrangement. TERT promoter mutation (85.3%) was the most common alteration, which was consistent with results of a previous study . The hot spots of TERT promoter mutation were situated at the − 124 bp and − 146 bp from the TERT ATG start site . The most frequent mutation was c.-124C > T (85.3%) in our cases. But we only found one case with mutation of c.-146C > T. Except for the two hot spots, we also found a A > C substitution at the − 57 bp, which had been reported in melanoma . Other alterations of TERT gene just occupied a small proportion.
Telomeres are DNA-protein structure located at the end of chromosomes. Telemeres shorten accelerates along with the round of cell division and leads to cell death finally . Cancer cells keep continuous division by reactivation of telomerase and maintaining of telomere length. Telomerases are in charge of the telomere synthesis, which consist of TERT, telomerase RNA component and core enzyme . Reactivation of telomerase is a crucial event in hepatocarcinogenesis . There are four mechanisms of telomerase reactivation: (a) thourgh TERT promoter mutations, (b) through HBV insertion into promoter, (c) through TERT amplification and (d) through TERT translocation . TERT controlled the activity of telomerase and is suppressed in most cells of adults . TERT mutations would lead to the overexpression of TERT [25–27].
In this study, we didn’t find the significant correlation between TERT mutations and clinicopathological characteristics of HCC patients such as tumor size, tumor number, MVI, BCLC stage and differentiation. The result was similar with the researches of Kwa et al  and Lee et al . Previous studies have reported that TERT mutations could lead to overexpression of TERT in several cancers. For example, transcriptional activity of TERT with c.-124C > T, c.-146C > T or c.-57A > C was higher than wild type in melanoma [23, 30]; Cao et al  reported that amplification of TERT increase the expression of TERT; Bayard et al  reported that rearrangement of TERT could induce overexpression of TERT. In survival analysis, we found that TERT mutations correlated with shorter TTP and OS of HCC patients underwent hepatectomy. We inferred that this result might be related with the overexpression of TERT caused by TERT mutation. Jeong et al  reported that TERT overexpression predicted poor intrahepatic recurrence free survival, this result was similar with ours. Besides, we found that BCLC stage and TERT mutations were independent risk factors for recurrence within 2 years after hepatectomy. A predictive model based on the BCLC stage and TERT mutations showed better predictive value for early recurrence after curative hepatectomy than any single factor. Patients with both BCLC stage B and TERT mutations had poorer prognosis than others. The predictive model may help us to identify patients with high risk of recurrence after hepatectomy. For these patients, more frequent surveillance and intervene in time was of vital importance.
This study has some limitations. First, this is a monocenter and retrospective study, multicenter and prospective studies are needed to acquire more representative and convincing results. Second, all patients enrolled were with HBV infection and without other hepatitis virus. Thus, our result may not applicable to HCC patients infected with other hepatitis virus. Third, due to the limitation of sample size, we couldn’t analyze the correlation between different mutations of TERT and prognosis of HCC patients.