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Ma et al. Hepatoma Res 2019;5:8  I  http://dx.doi.org/10.20517/2394-5079.2018.104                                                 Page 3 of 12


               Table 1. Telomerase reverse transcriptase promoter mutations in multiple cancers
                                                         Number of different types of TERT
                                   Number    Number          promoter mutations**
                Cancer type       of cancer   of TERT                                   Methods       Ref.
                                    cases   mutations*   C228T     C250T   C228T or
                                                                            C250T
                Cancer tissue
                   Glioma,         1230     231 (18.8)  179 (77.5)  48 (20.8)  227 (98.3)  PCR/Sanger sequencing  [28]
                   medulloblastoma,
                   hepatocellular
                   carcinoma, etc.
                   Bladder cancer, liver   1581  426 (26.9)  /    /        /        Whole-genome/low-  [25]
                   cancer, glioma, etc.                                             pass whole-genome
                                                                                    sequencing
                   CNS cancers     1515     327 (21.6)  257 (78.6)  68 (20.8)  325 (99.4)  PCR/bidirectional   [29]
                                                                                    sequencing
                   CNS, bladder, thyroid   741  142 (19.2)  99 (69.6)  43 (30.3)  140 (98.6)  PCR/Sanger sequencing  [36]
                   cancers, etc.
                   Urogenital cancers  302  130 (43.0)  100 (76.9)  24 (18.5)  124 (96.4)  PCR/Sanger sequencing  [37]
                   Medulloblastoma  466     98 (21.0)   /         /        /        PCR/Sanger sequencing  [35]
                   Melanoma        287      109 (38.0)  51 (46.8)  40 (36.7)  91 (83.5)  PCR/Sanger sequencing  [32]
                   Bladder cancer  262      218 (83.2)  165 (75.7)  32 (14.7)  197 (90.4)  SNaPshot assay and   [34]
                                                                                    Sanger sequencing
                   Melanoma        77       24 (31.2)   7 (29.2)  5 (20.8)  12 (50.0)  High-throughput   [33]
                                                                                    sequencing/Sanger
                                                                                    sequencing
                Cancer cell line
                   Melanoma        168      125 (74.4)  46 (36.8)  64 (51.2)  110 (88)  High-throughput   [33]
                                                                                    sequencing/Sanger
                                                                                    sequencing
                   Melanoma, liver,   150   24 (36.0)   /         /        24 (100)  Whole-genome     [26]
                   bladder cancers, etc.                                            sequencing, Sanger
                                                                                    sequencing,
                   Urothelial bladder   23  20 (87.0)   16 (80.0)  2 (10.0)  18 (90.0)  PCR/Sanger sequencing  [31]
                   cancer
                   Urothelial bladder   32  28 (87.5)   25 (89.3)  3 (10.7)  28 (100)  PCR/Sanger sequencing  [30]
                   cancer

               *Percentage in all cancer cases; **percentage in telomerase reverse transcriptase (TERT) mutation cases

               Overall, it is widely accepted that glioma, melanoma, bladder cancer and HCC are among those commonly-
               affected by TERT promoter mutations [25,28,38] .


               TERT PROMOTER MUTATIONS IN HCC
               The genomic landscape of HCC involves a number of pathways as well as somatic mutations in a wide range
               of genes, including TP53, CTNNB1, AXIN1, CDKN2A, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1,
                                                     [6]
               MLL2, and several epigenetic modifications . Despite the complexity of the genomic landscape of HCC,
               the single most significant factor is genomic changes on TERT promoter, which include point mutations,
               hepatitis B virus (HBV) DNA integrations, amplifications and epigenetic modifications. TERT promoter
               point mutations contribute more frequently (54%-60%) to the reactivation of telomerase in HCC than the
                                                                                                       [6-8]
               exclusively-present HBV insertions in the TERT promoter (10%-15%) and TERT amplification (5%-6%) .
               Therefore, we are going to thoroughly discuss TERT promoter mutations while briefly touching upon other
               genomic and epigenomic alterations on TERT promoter in HCC.


               TERT promoter point mutations
               A few prominent studies on HCC demonstrated that TERT promoter mutations were found in about 30%-60%
               of the total cases [8,39-49] . Consistent with the findings in other cancer types, the two most common mutations
               were C228T and C250T, and the former was more prevalent than the latter in HCC [Table 2] [8,39-47] . As shown
               in Table 2, there are no cases with both C228T and C250T mutations, which implies that these two hot spot
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