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[98]
immortalization . Anyhow, there are only a few studies focusing on the mechanisms of TERT promoter
mutations in HCC. Whether it shares the same mechanisms with other cancers requires further research in
the future.

TERT PROMOTER MUTATIONS IN DIAGNOSIS, PROGNOSIS AND THERAPY OF HCC
A study detected the TERT promoter mutations in plasma cell-free DNA (cfDNA) in 218 patients with HCC,
and the prevalence of TERT mutations was 47.7%, which was similar to the prevalence (44.4%) of 196 HCCs
[57]
derived from the TCGA database . Meanwhile, they also measured the prevalence of TERT promoter
[57]
mutations in cfDNA of 81 patients with cirrhosis, and the frequency was 8.6% . Since the frequency of
TERT promoter mutations gradually increases during the process of cirrhosis and liver cancer, the TERT
promoter mutations in the cfDNA in the serum can be detected as an important index for evaluating the
development of HCC. However, there still remains a problem with specificity since the TERT promoter
mutation is very common in various tumors so that the mutations in cfDNA cannot accurately reveal the
source of the lesion.

[7]
[43]
The prognostic value of TERT promoter mutations remains controversial. Kawai-Kitahata et al. and Huang et al.
performed survival analyses and demonstrated that TERT promoter mutations were associated with poor
[95]
overall survival and could be prognostic markers for HCC [7,43] . However, Ko et al. found that the presence
of TERT promoter mutations alone did not translate into poor prognosis, but that the SNP rs2853669 and
[39]
the -124C>T mutation combined were associated with poor survival rates. Further, Lee et al. reported
that longer telomere length, but not TERT promoter mutations, was independently associated with poor
overall survival. Besides showing TERT promoter mutations’ correlation with poorer overall survival
[99]
in HCC, Li et al. also demonstrated that TERT amplifications were associated with shortened overall
survival independent of other clinicopathological parameters such as age, gender and TNM staging. Thus,
while we are sure that genetic changes at TERT gene have prognostic value, we are uncertain about exactly
which factor(s) - TERT promoter mutations alone, the combination of the SNP rs2853669 and the -124C>T
mutation, longer telomere length or TERT amplifications - directly indicate(s) poor prognosis.

It is believed that TERT is a promising but also challenging driver gene to target. There are no drugs
specifically targeting TERT gene yet, although a few inhibitors have been used to target amplified genes in
HCC: epidermal growth factor receptor inhibitors like Gefitinib targeting amplified EGFR, MET, MAPK1,
MAPK3 and CRKL, Crizontinib and vemurafenib targeting BRAF and ERBB2, and alisertib targeting
[99]
amplified AURKA . According to Dhanasekaran et al. [100] , the somatic mutations associated with liver
tumor development lie in genes whose products are not easily or safely targeted, and that mutant TERT,
TP53, CTNNB1, and MYC are even believed to be undruggable. Nevertheless, the study also reveals that
a synthetic TERT DNA vaccine, INO-1400, is being tested in a phase 1 trial of patients with solid tumors
(NCT02960594) and that some trials are using TERT promoter mutation as a biomarker for study enrollment
(NCT02766270) [100] . Since a traditional strategy to target TERT is challenging, it is suggested that new
strategies, such as microRNA-based therapeutics, should be developed to target driver genes like TERT
or their pathways [100] . In fact, one study explored the potential of a novel immunotherapy using TERT-
derived peptide (TERT461) as a vaccine by investigating its safety and immunogenicity and characterizing
the TERT-specific T cell responses induced [101] . Their results showed that the vaccination induced TERT-
specific immunity in 10/14 (71.4%) of the patients, and that 57.1% of patients treated with TERT461 peptide-
specific T cells could prevent HCC recurrence after vaccination [101] . Another study also concluded that
CypB, SART2, SART3, p53, MRP3, AFP, and TERT are promising tumor-associated antigens (TAAs) in
HCC immunotherapy [102] . Besides, not only do they suggest that the administration of the TAAs or peptides
containing their epitopes as vaccines after HCC treatment is likely to be effective, but they also demonstrated
that the concurrent use of anti-CTLA-4 antibodies may further improve antitumor immunity [102] . Therefore,