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Alonso-Peña et al. Cancer Drug Resist 2019;2:680-709 I http://dx.doi.org/10.20517/cdr.2019.006 Page 695

for the double stranded end joining. Somatic mutations in XLF gene occur at a very low frequency in HCC
tumors. However, both in vitro and in vivo experiments have demonstrated that XLF knockdown confers
sensitivity to drug chemotherapy, suggesting that XLF-mediated increase in NHEJ activity can play a role
among mechanisms of chemoresistance in HCC .
[139]
The frequency of somatic mutations in DNA repair genes with clinical impact in CCA is unknown.
Nevertheless, the multicenter retrospective study of CCA patients mentioned above also reported enhanced
OS of CCA patients harboring somatic mutations suspected to be pathogenic in BRCA1/2 when treated with
platinum-based therapy [132]

Survival pathways and apoptosis (MOC-5)
Most pharmacological regimens currently used in the clinical treatment of cancer are based on the
activation of apoptosis in cancer cells. Therefore, impairment of the involved machinery not only results in
an uncontrolled cell growth, but also confers resistance to chemotherapy. The lack of response to anticancer
drugs may be caused by deregulated expression and the appearance of loss-of-function mutations in pro-
apoptotic factors (MOC-5a) or be due to an aberrant activation of anti-apoptotic proteins (MOC-5b) .
[39]
Somatic mutations affecting MOC-5a and MOC-5b genes in PLC are listed in Tables 7 and 8, respectively.

Alteration in the expression and/or function of pro-apoptotic factors (MOC-5a)
The TP53 gene encodes p53, which plays a key role as a tumor suppressor in several processes in response
to cellular stress signals, regulating the transcription of many genes involved in cell cycle arrest, apoptosis,
senescence, DNA repair and maintenance of genomic stability, among others. TP53 is one of the most
frequently mutated genes in HCC (25%-30%) . Most of these mutations affect the DNA-binding domain
[140]
of the protein, reducing its binding affinity to specific sequences of target genes. Cells harboring non-
functional protein are less likely to induce apoptosis and, therefore, more resistant to DNA damage caused
by chemotherapy , which has clinical consequences in HCC patients . A very common TP53 missense
[141]
[142]
mutation in HCC is c.747G>T (p.Arg249Ser), whose incidence has been related to exposure to aflatoxin .
[143]
In a study carried out in 409 HCC patients, c.747G>T (p.Arg249Ser) and c.469G>T (p.Val157Phe) mutations
have been associated with poorer prognosis . Another p53 mutation, c.743G>A (p.Arg248Gln), induces
[143]
resistance to doxorubicin and paclitaxel in HCC. Cells harboring that mutation display enhanced expression
of MDR1 , which is a known to be able to export both drugs.
[144]
Transcription factors related to p53, such as p63 and p73 are expressed as several isoforms due to alternative
splicing. Although TAp63 and TAp73 isoforms are considered as tumor suppressors with pro-apoptotic
activity [145,146] , N-terminal truncated isoforms, ∆Np63 and ∆Np73, display anti-apoptotic activity and
stimulate proliferation. TAp63 and TAp73 down-regulation, and ∆Np63 and ∆Np73 overexpression have
been found in HCC and they are related to shorter OS and tumor recurrence . In addition, in vitro studies
[147]
in HCC cells revealed that ΔNp63 isoform confers resistance to doxorubicin and mitoxantrone through the
inhibition of factors involved in mitochondrial apoptosis pathways .
[148]
TP53 is also frequently mutated in CCA . High expression of the truncated ∆N isoform ∆133p53, observed
[149]
in CCA tissues, has been correlated with poor clinical outcome in patients suffering from this PLC .
[150]
Moreover, ∆133p53 isoform expression is increased in 5-FU-resistant CCA cells . On the other hand, the
[151]
presence of mutations in TP53 and CDKN2A genes has been associated with poor prognosis in advanced
CCA patients receiving a combination of gemcitabine and platinum-derived drugs as first-line therapy .
[152]
Low levels of the pro-apoptotic factor TAp73 contribute to chemoresistance in CCA. Thus, TP73 expression
is decreased in 5-FU-resistance CCA cell lines . Deregulation of other pro-apoptotic proteins influences
[153]
the response to anticancer drugs commonly used in CCA treatment. For example, decreased expression of