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Page 2 of 12 Ma et al. Hepatoma Res 2019;5:8 I http://dx.doi.org/10.20517/2394-5079.2018.104

and molecular landscape of HCC in order to develop target therapies. The genetic landscape of HCC is
complicated and involves a number of pathways as well as a considerable amount of somatic mutations in a
[6]
wide range of genes . Among all these genetic alterations, telomerase reverse transcriptase (TERT) promoter
[6-8]
mutations occur most frequently, affecting ~60% of all HCC patients . In this mini-review, we mainly
summarize the frequency, mechanisms and clinical prospect of TERT promoter mutations in HCC. To
provide more background information, this review also briefly touches upon the TERT promoter mutations
in various cancers, although HCC remains the main focus of our discussion throughout the whole paper.

THE STRUCTURE AND FUNCTION OF TERT
Human telomerase is a ribonucleoprotein polymerase that reverses the continuous telomere shortening in
[9]
cell division by adding 5’-TTAGGG-3’ repeats to the ends of chromosome . It consists of two core subunits:
the catalytic component TERT and the RNA component (TERC) that serves as a template for elongating
telomeres [10,11] .

The TERT component is encoded by the TERT gene, located on chromosome 5 in humans. It spans a length
[12]
of about 40,000 base pairs (bp) with 16 exons . Of note, the TERT gene is suppressed in most normal
somatic cells (excluding germ cells and stem cells), ensuring that these cells only divide a finite number of
times and do not surpass the Hayflick limit [13,14] . Normal somatic cells stop dividing when their telomeres
[15]
become critically short, whereupon they enter a stage called senescence . Cancer cells, however, overcome
replicative senescence and achieve immortality by reactivating the TERT gene and upregulating TERT
[14]
expression .

The regulation of TERT expression largely depends on the activity of the TERT promoter, especially the
core functional fragment that consists of a 260 bp DNA sequence with several transcription factor binding
sites, but distinctly lacking a TATA box or a similar sequence [16,17] . The binding motifs in the TERT promoter
include two evolutionarily-conserved E-boxes (CACGTG), located at -242 bp and -34 bp to the translational
[18]
start site, for c-Myc binding . The binding of c-Myc to the E-box activates TERT transcription, suggesting a
role of c-Myc in regulation of the expression of TERT [19,20] . GC-boxes (GGGCGG), the binding sites for zinc
[21]
finger transcription factor Sp1, are the other characteristic sequences in the TERT promoter region . There
are at least five GC-boxes within the core promoter of TERT, and they function synergistically to maintain
[22]
the promoter activity of TERT . P53 has been shown to down-regulate TERT transcription in an SP1-
[23]
dependent manner .

TERT PROMOTER MUTATIONS IN SEVERAL CANCERS
TERT promoter mutations are the most frequent somatic mutations in a variety of cancers. It has been
widely reported that the two most common types of recurrent TERT promoter mutations are C228T and
C250T, located at positions 1,295,228 and 1,295,250 on chromosome 5, or -124 bp and -146 bp of the ATG
translational start site of the TERT gene [24-27] . In a systematic analysis involving 1,581 cancer cases of different
[25]
[28]
types, 27.0% were found to have TERT promoter mutations . Killela et al. examined 1,230 tumor
specimens of 60 different types and identified 231 TERT promoter mutations (18.8% of the total), among
which C228T and C250T mutations accounted for 98%. Similarly, in a study where 1,515 tumors of the
central nervous system were tested, 327 (21.6%) had TERT promoter mutations, and all except two contained
[29]
either C228T or C250T . Another study examined 150 cell lines of several cancer types from the Cancer
[26]
Cell Line Encyclopedia and noted that 24 cell lines (16%) harbored either C228T or C250T mutations .
Statistics show that C228T is somewhat more prevalent than the C250T mutation [Table 1] in a wide range
of cancer types, including various subtypes of CNS cancers, urogenital cancers, melanoma and thyroid
cancer [25,26,28-37] .