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Page 4 of 18 Caron de Fromentel et al. Hepatoma Res 2020;6:80 I http://dx.doi.org/10.20517/2394-5079.2020.77

In response to a wide variety of intrinsic and extrinsic stress signals, such as DNA damage, oncogenic
activation or hypoxia, p53 is subjected to a number of post-translational modifications, including
phosphorylation at multiple N- and C-terminal sites by Chk1/2, CK1/2, DNA-PK and other kinases.
Phosphorylation usually blocks the binding of E3-Ubiquitin ligases, resulting in both stabilization and
[27]
conformational shift of p53 from a latent to an activated state . Stabilization and activation are remarkably
fine-tuned processes that depend not only on the type and intensity of the signal, but also on the cell
[28]
type and its differentiation state , leading to the transactivation of canonical p53-target genes. p53
[29]
activation translates into various cellular processes, such as cell cycle arrest , DNA repair , allowing cell
[30]
[33]
[31]
[32]
survival, or apoptosis , autophagy and ferroptosis , causing the death of damaged cells. Thereby, p53
response enables the maintenance of genomic stability and prevents the emergence of pre-malignant cells.
Accordingly, tp53 knock-out mice or tp53 knock-in mice expressing an inactivated form of p53, are prone
to developing spontaneous tumors . Importantly, p53 activities do not depend on transactivation only and
[26]
the interaction between p53 and other cellular proteins has also been implicated in its tumor suppression
function . In addition, besides cell-cycle arrest and cell death the regulation of other cellular processes,
[34]
including metabolism, cell migration (by blocking epithelia-mesenchymal transition) or induction of
differentiation, contributes to the tumor suppressor function of p53 [35,36] . The repertoire of functions,
pathways and genes regulated by p53, p63 and p73 has progressively widened well beyond cell fate, tumor
suppression and development. p53 family members have been so far involved in reproduction, genomic
repair, fidelity and recombination, metabolic processes, longevity, stem cell biology, adaptive immunity and
T cell functions and changes in epigenetic marks [26,37] .

TP53 MUTATIONS AND THEIR CONSEQUENCES ON LIVER TUMORIGENESIS
Unlike TP63 and TP73 genes, which are rarely lost or mutated in tumors, genetic alterations of the TP53
gene are frequently observed, but in contrast to other tumor suppressor genes, the deletion of the two
[38]
alleles is a rare event . Strikingly, more than 50% of human tumors present a missense (or less frequently a
nonsense or frame shift) mutation in one TP53 allele, frequently accompanied by the deletion of the other
[39]
one (loss of heterozygosity, LOH) . The location of the mutation depends on numerous parameters, such
as cell type and the tumor-inducing agent. Nevertheless, some codons (175, 245, 248, 249, 273 and 282)
have been found to be preferentially mutated and defined as “hot spot” codons. Mutations of these hot
spots can be classified in two categories, those affecting p53 conformation (175, 245, 249, 282) and those
that lie in the DNA contact domain (248, 273) . All block p53 binding to the cognate p53REs. Altogether,
[40]
these six mutations account for more than 25% of the missense and nonsense mutations listed in the IARC
[41]
TP53 database R20, (https://p53.iarc.fr/) . Figure 2A illustrates the distribution of the resulting substituted
amino acids along the p53 protein (only those for which more than 100 mutations have been reported in
the database are shown). Most of the mutations are located in the DBD, mostly resulting in the inability of
mutant p53 (mutp53) to bind p53RE and thus to transactivate p53-target genes (Figure 3, left upper panel).
The mutation at codon 249 represents a particular case among the hot spots, because it is overrepresented
in HCC. Figure 2B clearly shows the high prevalence of this mutation in HCC (around 30%), whereas
the five other hot spots account for only 9%. Interestingly, the arginine residue at codon 249 is almost
exclusively changed to a serine residue (96%) in HCC, due to a G/C to T/A transversion. Transversions
in the TP53 gene are also found in several other types of cancer, such as those affecting the respiratory
and urinary tracts, whereas G/C to A/T transitions are mainly present in colorectal carcinomas or brain
tumors. Whereas transitions are expected to be due to intrinsic factors, transversions are correlated with
exposure to environmental mutagens that form DNA adducts and often affect particular codons, as in the
TP53 gene . For example, TP53 codons 157 and 158 are targets of tobacco smoke compounds in lung
[42]
adenocarcinoma. Similarly, in HCC the G/C to T/A transversion at codon 249 is caused by consumption of
AFB1-contamined food [43-46] . AFB1 exposure is mainly observed in sub-Saharan Africa and Southeast Asia,
two regions in which HBV chronic infection is frequent. The combination of these two extrinsic factors
has been shown to be responsible for the high incidence of HCC in these regions and to be associated