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Page 4 of 12 Ma et al. Hepatoma Res 2019;5:8 I http://dx.doi.org/10.20517/2394-5079.2018.104

Table 2. Telomerase reverse transcriptase promoter mutations in hepatocellular carcinoma
Number of different types of TERT promoter
Number of HCC Number of TERT mutations (%*)
cases mutations (%) C250T or Methods Ref.
C228T C250T
C228T
469 254 (54.2) 236 (92.9) 11 (4.3) 247 (97.2) PCR/bidirectional [8]
sequencing
316 103 (32.6) 96 (93.2) 5 (4.9) 101 (98.1) PCR/Sanger sequencing [43]
305 179 (58.7) 166 (92.7) 11 (6.1) 177 (98.9) PCR/Sanger sequencing [42]
276 85 (30.8) 84 (98.8) 1 (1.2) 85 (100) PCR/Sanger sequencing [44]
196 87 (44.4) / / / Whole-genome sequencing [48]
195 57 (29.5) 54 (94.7) 3 (5.3) 57 (100) PCR/Sanger sequencing [45]
160 46 (28.8) 32 (69.6) 14 (30.4) 46 (100) PCR/Sanger sequencing [39]
44 15 (34.1) 10 (66) 5 (34) 15 (100) PCR/Sanger Sequencing [40]
190 57 (30.0) 50 (87.7) 7 (12.3) 57 (100) PCR/bidirectional [46]
sequencing
127 64 (50.4) 62 (96.9) 2 (3.2) 64 (100) PCR/Sanger sequencing [47]
123 45 (36.6) 43 (95.6) 2 (4.4) 45 (100) PCR/Sanger sequencing [41]
125 85 (68.0) / / / PCR/Sanger sequencing [49]
*Percentage in telomerase reverse transcriptase (TERT) mutation cases. HCC: hepatocellular carcinoma

mutations are mutually exclusive. Furthermore, a comprehensive review evaluating the distribution of TERT
promoter mutations in 1,939 primary HCC from four continents also showed that TERT promoter mutations
had almost the same level of prevalence in all continents, with slightly higher mutation rates in Europe
(56.6%) and Africa (53.3%) than in America (40%) and Asia (42.5%), and that C228T mutation was universally
[1]
more frequent than C250T .

Apart from the high frequency of TERT promoter mutations in HCC, another piece of useful information
indicated by several lines of evidence is that TERT promoter mutations are associated with a few factors,
including virus status, gender, age and tumor size of the patients. TERT promoter mutations were more
frequent in HCC patients infected with hepatitis C virus [7,8,39,41,42,47,48,50] than in those infected by HBV. One
study suggested that this phenomenon could be explained by the high rate of HBV DNA insertions in
[42]
the TERT promoter . Furthermore, several studies reported higher TERT promoter mutations rate in
[42]
[51]
men [7,39,42] , in older patients [7,50] , in patients with smoking , in patients with smaller tumors , in patients
[42]
with low serum levels of alpha-fetoprotein , and in patients with CTNNB1 mutations [8,42,47] , while other
papers either disagreed with or did not find these associations.
Further, TERT promoter mutations are early somatic genetic alterations in hepatocarcinogenesis, playing
important roles in malignant transformation of preneoplastic cirrhotic lesions [42,52] . Nault et al. found that
[52]
the frequency of TERT promoter mutations increased as premalignant lesions transformed into HCC, from
6% in low-grade dysplastic nodules and 19% in high-grade dysplastic nodules to 61% in early HCC and 42%
in small and progressed HCC; mutations in 10 other recurrent genes only emerged in small and progressed
[43]
HCC. Similarly, Huang et al. demonstrated that the mutation rates also increased in a stepwise manner
[53]
during advanced HCC progression and reached a maximum of 45% in patients with stage C. Calderaro et al.
found that there were 64.6% (208/322) cases with TERT promotor mutations; HCC phenotypes were tightly
associated with gene mutations, including TERT promoter mutations, and transcriptomic classification.

As the proportion of nonalcoholic fatty liver disease (NAFLD)-related HCC patients is increasing due to
increased prevalence of metabolic syndrome, especially in Western countries [54-56] , there have been studies
investigating TERT promoter mutations in NAFLD-related HCC. One research analyzed the genetic
aberrations of 11 tumor samples from 10 NAFLD-HCC patients and found that TERT promoter mutation
[56]
C228T occurred in 9/11 (82%) cases . On the contrary, in another study, the prevalence of TERT promoter
mutations C228T and C250T was very low (3.2%) in patients with NAFLD . Obviously, the TERT promoter
[57]
mutation state in NAFLD-related HCC is far from conclusive.